Concise total syntheses of dipiperidine alkaloids virgidivarine and virgiboidine through Ru-mediated Ene-Ene-Yne ring rearrangement metathesis (RRM)

Article abstract of DOI:10.1002/ejoc.201201516

Herein, we report on the first enantioselective synthesis of the sparteine-type alkaloids virgidivarine (1) and virgiboidine (2). The stereoselective construction of the challenging dipiperidine core within 1 and 2 was realized by applying an intramolecular ene-ene-yne ring-rearrangement metathesis (RRM) protocol. In combination with this sequence, an unprecedented tandem metathesis/oxidation reaction was established. Subsequent to the RRM event, the Ru-alkylidene species was converted into the highly potent dihydroxylation catalyst RuO₄ by the addition of NaIO₄. This transformation rendered five sequential reactions that include an ene-ene-yne RRM/dihydroxylation/glycol cleavage in a one-pot procedure. This approach provides practical and general access to dipiperidines and piperidino-quinolizidines. Despite their wide use in organic and organometallic chemistry as well as their occurrence in biologically active natural products, methods are still lacking for the stereoselective synthesis of these motifs. Five@Once: A new method to access dipiperidine and piperidino-quinolizidine alkaloids was established within the total syntheses of virgidivarine (1) and virgiboidine (2). The key step includes a Ru-mediated intramolecular (tandem) ene-ene-yne ring-rearrangement metathesis/oxidation process, in which a sequence of five reactions occur in a single vessel with one catalyst source. Copyright

Full text of DOI:10.1002/ejoc.201201516

FULL PAPER
DOI: 10.1002/ejoc.201201516
Concise Total Syntheses of Dipiperidine Alkaloids Virgidivarine and
Virgiboidine through Ru-Mediated Ene-Ene-Yne Ring Rearrangement
Metathesis (RRM)
Steffen Kress,[a] Jochen Weckesser,[a] Sabrina Renate Schulz,[a] and Siegfried Blechert*[a]
Keywords: Total synthesis / Domino reactions / C–C coupling / Homogenous catalysis / Metathesis / Alkaloids / Nitrogen
heterocycles
Herein, we report on the first enantioselective synthesis of
the sparteine-type alkaloids virgidivarine (1) and virgiboid-
ine (2). The stereoselective construction of the challenging
dipiperidine core within 1 and 2 was realized by applying an
intramolecular ene-ene-yne ring-rearrangement metathesis
(RRM) protocol. In combination with this sequence, an un-
precedented tandem metathesis/oxidation reaction was es-
tablished. Subsequent to the RRM event, the Ru-alkylidene
species was converted into the highly potent dihydroxylation
catalyst RuO4 by the addition of NaIO4. This transformation
rendered five sequential reactions that include an ene-ene-
yne RRM/dihydroxylation/glycol cleavage in a one-pot pro-
cedure. This approach provides practical and general access
to dipiperidines and piperidino-quinolizidines. Despite their
wide use in organic and organometallic chemistry as well as
their occurrence in biologically active natural products,
methods are still lacking for the stereoselective synthesis of
these motifs.
tathesis transformation, a new catalytically active species
can be generated and used for nonmetathesis reactions such
as hydrogenations, olefin isomerizations, and oxidations.[7]
These processes not only offer an efficient means for using
costly catalysts, but also significantly reduce the number of
purification procedures. Herein, we report the total synthe-
ses of virgidivarine (1) and virgiboidine (2) by using an in-
tramolecular domino ene-ene-yne RRM approach (RCM-
ROM-enyne-RCM, RCM = ring-closing metathesis, ROM
= ring-opening metathesis) that is combined with an oxidat-
ive C–C bond cleavage to provide concise access to these
challenging structural motifs.
Introduction
Recently, the structural motifs of dipiperidine and piper-
idino-quinolizidine alkaloids have attracted considerable
interest in the field of target-oriented synthesis. Not only
are they found in several promising pharmacologically
active compounds (e.g., cytisine,[1] matrine,[2] and nanka-
kurines[3]), but also their unique structural characteristics
(e.g., sparteine[4] and its surrogates)[5] have led to their ex-
tensive use in the field of asymmetric synthesis. Surpris-
ingly, examples for an efficient asymmetric construction of
the dipiperidine core remain rare. The synthetic difficulty
resides in the enantioselective formation of the contiguous
stereocenters at C-4 and C-6 (see Scheme 1), which include
the connection between the piperidyl moieties. During re-
cent years, Ru-mediated ring-rearrangement metathesis
(RRM) processes that involve more than two consecutive
metathesis transformations have been shown to be highly
effective as a flexible tool for the construction of intricate
carbo- and heterocycles.[6] The growing interest with regard
to tandem processes, which is driven by the necessity for
more economic, efficient, and environmentally benign pro-
cesses, has led to the development of versatile protocols.
When an organometallic alteration of the Ru-based me-
tathesis catalyst occurs subsequent to a respective me-
[a] Institut für Chemie, Technische Universität Berlin,
Straße des 17. Juni 135, 10623 Berlin, Germany
Fax: +49-30-31429745
E-mail: blechert@chem.tu-berlin.de
Scheme 1. Structures of virgidivarine (1) and virgiboidine (2)
(above) as well as strategy for the synthesis of the dipiperidine scaf-
fold (below).
Homepage: http://www.chemie.tu-berlin.de/blechert
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201516.
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Total Syntheses of Dipiperidine Alkaloids
Virgidivarine (1)[8] and virgiboidine (2)[9] were first iso- planned to set the targeted (R) configuration at C-2. In the
lated in 1982 by van Eijk and de Kok from the leaves of case of poor selectivity, the C–H acidity at C-2 might be
African Leguminosae Virgilia divaricata and Virgilia oro- used to equilibrate a diastereomeric mixture to the thermo-
boides. Because only minor quantities of 1 and 2 were ex- dynamically favored all equatorial system through a base-
tracted and isolated, an investigation regarding their bio- mediated process. The crucial metathesis precursor II
logical activity has not yet been achieved. Virgiboidine (2), should arise from an initial Mitsunobu-type C–N coupling
a piperidino-quinolizidine, represents the dehydrated deriv- reaction between a suitable propargylic amide and 1,2-
ative of 1, and both alkaloids belong to the class of sparte- trans-disubstituted primary alcohol III, which is readily
ine compounds.
available on a multigram scale.
Our synthesis commenced with the preparation of
alcohol 7,[11] which was derived by an optimized protocol
as depicted in Scheme 3. Monoacetate 3, which was ob-
tained on a 50 g scale by an enzymatic desymmetrization of
the corresponding diacetate,[12] represents the starting point
for this approach.
Results and Discussion
As depicted in Scheme 1, the core structure of 1 is char-
acterized by two piperidine moieties that are connected by
the tertiary stereogenic centers at C-4 and C-6. The trisub-
stituted ring system B contains a carboxyl group at the
stereogenic C-2 as well as an N-butenyl moiety. All of the
substituents reside in the thermodynamically favored equa-
torial positions, and, thus, 1,3-diaxial interactions are avo-
ided. The strategy for the total syntheses of virgidivarine (1)
and virgiboidine (2) is outlined in Scheme 2. Access to 2
was assumed to occur by an intramolecular amide bond
formation from 1.
Scheme 3. Synthesis of substrate 7. Reagents and conditions:
a) (i) allylNHNos, PPh3, diisopropylazodicarboxylate (DIAD),
tetrahydrofuran (THF), 0 °CǞr.t., 98% for 4; (ii) PhSH, K2CO3,
N,N-dimethylformamide (DMF), 60 °C, 96%; (iii) Boc2O (Boc =
tert-butoxycarbonyl), MeOH, 60 °C, 94%; (iv) KCN, MeOH, room
temp., 97%; b) KH, ICH2SnBu3,[14] dibenzo-18-crown-6, THF,
room temp., 90%; c) nBuLi, THF, –100 °CǞ–60 °CǞr.t., 74%.
This versatile building block (i.e., 3) allows for highly
flexible and stereoselective access to cis- or trans-substituted
cyclopentenes for employment in target-oriented synthesis,
and this strategy represents a variable approach to the
stereoselective construction of the C-4–C-6 bridge of the
targeted dipiperidines (see Scheme 1). Within this route, in-
version of the stereocenter at C-4 of 3, which sets the de-
sired trans configuration, was realized by introducing the
amide moiety under Fukuyama conditions in 98% yield.
Scheme 2. Key steps within the retrosynthetic analysis of 1 and 2
(PG = protecting group).
The key step for the stereoselective construction of the The p-nitrophenylsulfonyl (Nos) group was installed in this
dipiperidine scaffold in 1 is an ene-ene-yne domino RRM sequence to provide sufficient N–H-acidity for a Mitsu-
process. Previous studies by our group suggest that I should nobu-type coupling and was readily cleaved subsequent to
be accessible by a domino metathesis transformation of in- the C–N bond formation.[13]
termediate II. With respect to a RRM, five-membered rings
With the focus on an orthogonal protection strategy
are generally regarded as strained systems (i.e., a driving (vide infra), the nosyl system was readily replaced by a Boc
force), which reliably undergo ring rearrangement to their protecting group to furnish 5, after saponification of the
corresponding six-membered systems.
ester in 86% yield over the four steps. The second key trans-
On the basis of previous work in the area of tandem formation en route to 7 was a stereoselective [2,3] sigma-
olefin RCM/oxidation reactions, we envisage an oxidative tropic Wittig–Still rearrangement to generate the targeted
cleavage of the 1,3-diene system that is obtained upon 1,2-trans-disubstituted cyclopentenyl scaffold.[11] Therefore,
RRM by the selective transformation of the employed me- installation of the tributylstannylmethyl ether was achieved
tathesis catalyst. In contrast to common procedures, in by applying a Williamson protocol to provide 6 in 90%
which diols are obtained as the product derived from a tan- yield.[15] Subsequently, the rearrangement was initiated by
dem metathesis dihydroxylation reaction,[10] an additional generating the highly reactive α-lithiated species upon the
glycol cleavage was the target in this sequence. Beyond that, addition of nBuLi, and carefully controlling the reaction
a substrate-controlled diastereoselective hydrogenation was temperature gave 7 in 74% yield. In this sequence, alcohol
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S. Kress, J. Weckesser, S. R. Schulz, S. Blechert
FULL PAPER
7 was derived in an overall yield of 57% starting from 3, tive oxidation. A significant improvement was realized by
which set the stage for the forthcoming total syntheses. isolating metathesis product 9, which was followed by a
With 7 in hand, the targeted metathesis precursor 8 was stepwise oxidative cleavage that was initiated by a dihydrox-
accessed by a C–N coupling reaction with Nos-protected ylation under milder Sharpless conditions (87% brsm for
propargylamine[16] in an excellent yield of 82%, through the 10, see Scheme 4) and a subsequent glycol cleavage by em-
application of the Fukuyama protocol (see Scheme 4).[13] ploying NaIO4. Through this route, aldehyde 11 was ob-
Apart from the installation of the amide, an orthogonally tained in an excellent yield of 96% after purification (83%
protected system, which is essential for selective manipula- over two steps).
tions within ring system B, was established. Having realized
an efficient route to ene-ene-yne system 8, we proceeded to
investigate the pivotal RRM domino process. Exposure of
8 to metathesis catalysts resulted in a fundamental skeletal
reorganization, which converted readily assembled substrate
8 into the synthetically challenging dipiperidine core of the
target compounds. Among the standard metathesis cata-
lysts, a superior performance was observed in the presence
of catalyst 16 (5 mol-%, see Scheme 4) under one atmo-
sphere of ethylene to provide the corresponding product 9
in 83% isolated yield. Consistent with the studies of
Mori,[17] the presence of ethylene plays a key role for an
efficient transformation. The metathetically active Ru-
methylidene species is deactivated by the formation of less
reactive Ru-vinylidene complexes, upon a secondary me-
tathesis transformation that involves the 1,3-diene system
within the obtained product. In the presence of an excess
amount of ethylene, this reaction pathway is unfavored.
Thus, target product 9 was provided in a significantly de-
creased yield of just 15%, when the reaction was performed
under an atmosphere of nitrogen. In general, these RRM
processes tolerate a wide range of functional groups as well
as different moieties within the precursor to render a flexi-
ble approach to dipiperidine alkaloids. In spite of the tre-
mendous use of ene-yne RCM reactions in target-oriented
synthesis, tandem sequences that include metathesis and
Scheme 4. Reagents and conditions: a) C3H3NHNos, PPh3, DIAD,
THF, 0 °CǞr.t., 82%; b) Hoveyda–Blechert catalyst (16, 5 mol-%),
ethylene (1 atm, balloon), dichloromethane (DCM), 40 °C, 83%;
c) AD-mix-β, tBuOH/H2O, 0 °C, 48% (87% brsm); d) NaIO4/SiO2,
dihydroxylation combined with a subsequent glycol cleav-
age have not yet been reported, to the best of our knowl-
edge. The introduced oxidant should serve as co-oxidant
within the dihydroxylation process and enable a subsequent
glycol cleavage. Encouraged by our results based on model
studies of tandem ene-yne RCM/oxidation sequences to
MeCN/EtOAc, 96%; e) see (b) and then NaIO4/SiO2, MeCN/
EtOAc, 33% (42% brsm 9); f) (i) NaClO2, H2O2, NaH2PO4,
MeCN/H2O, 0 °C Ǟr.t.; (ii) CH2N2, DCM, room temp., 91%;
g) PhSH, Cs2CO3, MeCN/DMSO (98:2 v/v; DMSO = dimethyl
sulfoxide), 70 °C, 78%.
Having established efficient access to the targeted di-
provide piperidine-3-carbaldehydes in the presence of piperidine structure, the way was paved for the final stage
NaIO4/SiO2,[18] we proceeded to transfer these protocols to of the total syntheses. Strategically, we envisaged a late Boc
the current RRM operation to provide aldehyde 11 from deprotection would allow for selective manipulations within
8 in a one-pot procedure. Having elaborated an optimized ring B. Key transformations involve the installation of the
protocol for the synthesis of 9, we were confident of achiev- unsaturated N-butenyl group, which had to be realized after
ing a kinetically-controlled regioselective oxidative cleavage the diastereoselective hydrogenation. Oxidation and depro-
of the monosubstituted double bond within the 1,3-diene tection should provide targeted product 1. With regard to
system of 9 (see Scheme 4). This reaction was highly desir- this, our first approach is depicted in Scheme 4.
able, as five reactions (RCM/ROM/ene-yne-RCM/dihydrox-
Prior to the hydrogenation step, the Nos group in 11
ylation/glycol cleavage) would be conducted sequentially in needed to be cleaved, because of its incompatibility with
a single vessel. To our delight, this intricate multiple-step regard to hydrogenation conditions. This route represents
reaction furnished aldehyde 11, after the NaIO4-mediated the shortest access to the desired target by allowing for N-
oxidative cleavage of diol 10 in a notable yield of 33% [42% alkylation after reduction of the respective olefins to con-
based on recovered starting material (brsm) with regard to struct the full scaffold of the target compounds. To avoid
9], and once again, the high potential of Ru-mediated me- polymerization processes, aldehyde 11 was first converted
tathesis tandem processes was demonstrated. However, the into the corresponding methyl ester 12 by a Pinnick oxi-
diminished yield was attributed to the high reactivity of dation and proximate esterification of the crude product by
RuO4, which led to difficulties with respect to a regioselec- treatment with diazomethane (91% yield over two steps).
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Total Syntheses of Dipiperidine Alkaloids
Subsequent cleavage of the Nos group was effected by treat- readily transformed into the corresponding methyl ester by
ment of 12 with thiophenol and Cs2CO3 in MeCN/DMSO treating the crude product with diazomethane (see
(98:2, v/v)[19] to furnish 13 as a precursor to the forthcom- Scheme 5). With the objective to install the homoallylic
ing reduction in 78% yield.
moiety into ring B, a selective cleavage of the trifluoroaceta-
Surprisingly, the hydrogenation of 13 was problematic. mide in the presence of the methyl ester had to be ac-
First attempts were performed under standard conditions complished next.
by employing Pd/C in MeOH (r.t., 1 atm H2). After 24 h,
1
the H NMR spectrum of the crude product indicated in-
complete hydrogenation, and the appearance of new ole-
finic signals revealed intensive migration processes of the
double bonds. Even a prolonged reaction time (36 h) and
elevated temperatures (50 °C) did not afford the fully satu-
rated product. TLC analysis indicated the formation of a
complex product mixture under more forcing conditions.
Even an exhaustive screening of catalysts by employing, for
example, RaNi, PtO2, Rh/C, Ir/C, and Re/C under various
conditions did not allow for sufficient suppression of the
olefin migration. With regard to this, the best result was
achieved by using RaNi (90 °C, 90 bar H2) to provide the
product in a moderated yield of up to 50% [diastereomeric
ratio (dr) 2:1, as determined by integration of the methyl
ester signals within the H NMR spectrum].
Figure 1. X-ray crystal structure for 17. The dipiperidine core
structure is highlighted with the respective atom labels.
1
The protection of the free amine in 13 allowed for the
use of homogeneous catalysts, with which there is generally
less of a tendency for double-bond migration during hydro-
genation processes. Unfortunately, upon exposing Boc-pro-
tected 14 to Wilkinson catalyst (benzene, 50 °C, 15 bar,
24 h), only reduction of the disubstituted olefin in ring A
was observed, whereas the trisubstituted α-β-unsaturated
ester remained intact. The more reactive Crabtree catalyst
led to complete decomposition of the substrate under stan-
dard conditions.[20] Generally, heterogeneous systems have
been shown to be inadequate and lead to a fast isomeriza-
tion of the acceptor-substituted olefin into conjugation with
the Boc-protected amide, as indicated by a broad signal at
8.1 ppm in 1H NMR spectrum (to compare, see ref.[21]). The
introduction of the sterically less demanding and orthogo-
nal trifluoroacetamide group (in 15) did not improve the
results.
As a consequence of these findings, substrate 11 was re-
duced with diisobutylaluminum hydride (DIBAL-H) to the
corresponding alcohol 17 in 92% yield, which circumvented
the observed isomerization driven by the electron-with-
drawing group in 14 (see Scheme 4).[22]
The absolute configuration of 17 was confirmed by X-
ray crystal structure analysis, which proved the successful
construction of the C-4 and C-6 stereocenters within the
dipiperidine core structure (see Figure 1). Within this sec-
ond approach, the optimal conditions for the Nos cleavage d) (i) (COCF3)2O, pyridine, DCM, 0 °CǞr.t., quant. for 20;
were found by the intermediary protection of the hydroxy
Scheme 5. Reagents and conditions: a) (i) DIBAL-H, THF,
–78 °CǞr.t., 92% for 17; b) (i) ethyl vinyl ether (EVE), pyridinium
p-toluenesulfonate (PPTS), DCM, room temp., 96% for 18;
c) PhSH, K2CO3, MeCN/DMSO (98:2, v/v), 92% for 19;
(ii) HCl (0.5 m), acetone, room temp., quant. for 21; e) (i) PtO2 (Ad-
amЈs catalyst), H2 (1 atm), EtOAc, r.t.; (ii) PCC, DCM, r.t.;
(iii) NaClO2, H2O2, NaH2PO4, MeCN/H2O, 0 °C Ǟr.t.;
group in 17 as an ethoxyethyl acetal (i.e., 18, see Scheme 5).
Finally, the reduction succeeded for the trifluoroacetate-
(iv) CH2N2, DCM, r.t.; f) MeONa, molecular sieves (MS, 3 Å,
protected derivative 21, which was derived in 88% yield
from 17 as depicted in Scheme 5. In the presence of PtO2
(EtOAc, 1 atm H2), the saturated product was obtained (for
determination of dr, vide infra). Then, 22 was accessed by
using a pyridinium chlorochromate (PCC)/Pinnick oxi-
ground), DCM/MeOH (5:1 v/v), room temp., 41% for 23 over 7
steps from 19; g) 4-bromo-1-butene, K2CO3, MeCN, 80 °C, 84%;
h) trimethylsilyl chloride (TMSCl), MeOH, 50 °C, quant. for 25;
i) HCl (0.5 m), 80 °C, 95% for 1·2HCl; j) LiOH, D2O, room temp.,
quant.; k) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),
N-methylmorpholine (NMM), EtOH, room temp., 29%; (EE =
dation protocol to provide the carboxylic acid, which was ethoxyethyl).
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S. Kress, J. Weckesser, S. R. Schulz, S. Blechert
FULL PAPER
Besides the deprotection step, the equilibration of the un- 1·2HCl unequivocally proves the correct stereochemistry at
desired epimer to the desired all-equatorial product 23 was C-2, and all of the substituents within the trisubstituted
envisaged to occur under basic conditions in a one-pot reac- ring system B reside in equatorial positions.
tion. Common protocols, for example, employing Na2CO3
Finally, 1·2HCl was converted into virgidivarine (1) upon
or K2CO3 in MeOH,[23] provided a mixture of product 23 treatment with 2.0 equiv. of LiOH in D2O. The deproton-
and the respective free amino acid. However, the reaction ation was followed by NMR spectroscopy. The obtained
was realized by employing an excess amount of MeONa in spectroscopic data are consistent with those reported for
a mixture of DCM/MeOH (5:1) with ground and activated the isolated natural product.[8b] As depicted in Scheme 5,
MS (3 Å) to prevent saponification. Gratifyingly, under the final construction of the piperidino-quinolizidine scaf-
these conditions 23 was obtained as single diastereomer in fold was achieved by an EDC-mediated intramolecular
41% over seven steps (starting from 19, see Scheme 5) with- amide bond formation within 1 in the presence of N-meth-
out the need for an intermediary chromatographic purifica- ylmorpholine in ethanol.[24] The IR and EI fragmentation
tion. Interestingly, the use of MS (3 Å, beads) did not fur- spectra, which represent the only known analytical data so
nish an equilibrated product and provided instead a mixture far, were consistent with those obtained within this work.
of diastereomers in a diminished yield of 25% over seven In addition, we provide the full set of NMR spectroscopic
steps (dr 1:1.8 in favor of the targeted (R) epimer, deter- data for the cyclized product, which unambiguously con-
mined by integration of the methyl ester signals in 1H firms the proposed structure of virgiboidine (2).
NMR). This fact allows for an indirect determination of
the diastereoselectivity of the hydrogenation process, as the
Conclusions
use of the trifluoroacetamide protecting group did not al-
low for NMR spectroscopic analysis because of the forma-
tion of a complex mixture of rotamers. However, suitable
conditions were elaborated to access diastereomerically
pure 23.
In conclusion, we completed the first enantioselective to-
tal syntheses of virgidivarine (1) and virgiboidine (2) by
using an intramolecular ene-ene-yne domino RRM process,
which was successfully combined with an oxidative C–C
bond cleavage (tandem processes). This approach offers a
new pathway for the construction of the intricate dipiperi-
dine core structure, which in spite of its widespread use in
organic and organometallic chemistry as well as its occur-
rence in biologically active compounds, methods are still
lacking for its stereoselective synthesis.
N-Butenylation of secondary amine 23 was achieved un-
der standard alkylation conditions (K2CO3/MeCN), which
finally gave the full scaffold of the target structure. Despite
the use of an excess amount of 4-bromo-1-butene (7 equiv.),
which was necessary to reach full conversion by compensat-
ing the elimination processes, no quaternization was ob-
served during the reaction. Product 24 was obtained in 84%
isolated yield. Having installed the key architectural fea-
tures of 1, the remaining transformations comprised two
deprotection steps. Cleavage of the Boc group was realized
by exposing 24 to anhydrous HCl, which was generated by
TMSCl in dry methanol, to provide Boc-deprotected prod-
uct 25 in quantitative yield.
Experimental Section
General Methods: The reactions with air- and moisture-sensitive
components were performed under N2 using standard Schlenk
techniques. The 1H NMR (700, 500, and 400 MHz) and 13C NMR
(175, 125, and 100 MHz) spectroscopic data were obtained with
a Bruker AV-700, DRX-500, and DRX-400 Advance instrument,
respectively. In the case of rotameric mixtures, the NMR spectra
were recorded at high or low temperatures, and the heterotopic
methylene protons are marked as Ha and Hb. IR spectra were mea-
sured by attenuated total reflectance (ATR) with a Nicolet Magna-
IR spectrometer 750 and Jasco FTIR-4100. Melting points were
obtained by using a Leica Galen melting point apparatus with a
Wagner-Munz control unit. ESI mass spectra were measured with
a Thermo Scientific LTQ orbitrap XL. EI mass spectra were re-
corded with a Finnigan MAT 95 SQ by FAB ionization. Elemental
analyses were performed with a Perkin–Elmer 2400 CHN-S/O ele-
mental analyzer. Optical rotations were recorded with a Perkin–
Elmer Polarimeter 341 with the sample in solution in a 10 cm unit
cell at 589 nm [c (g/100 mL)]. The crystals were mounted on a glass
capillary in perfluorinated oil and measured in a cold flow of N2.
The data were collected with an Oxford Diffraction Xcalibur S
Sapphire at 150 K (Mo-Kα radiation, λ = 0.71073 Å). The struc-
tures were solved by direct methods and refined on F2 with the
SHELX-97 software package.
Subsequent saponification in HCl (0.5 m solution) fur-
nished the dihydrochloride of virgidivarine (1·2HCl) in 95%
yield. As depicted in Figure 2, the crystal structure of
CCDC-903631 (for 17) and -903632 (for 1·2HCl) contain the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Figure 2. X-ray crystal structure for 1·2HCl Ϫ the chlorides are not
displayed in this figure.
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Total Syntheses of Dipiperidine Alkaloids
Data Centre via www.ccdc.cam.ac.uk/data_request/cif. TLC analy-
ses were visualized by using KMnO4/H2O in addition to UV light
(254 and 366 nm) with fluorescent-indicating plates (silica gel,
Merck, 60 F 254, layer thickness 0.2 mm). The solvents were pur-
chased in absolute quality, or they were dried. THF was dried with
sodium/benzophenone, and DCM and n-hexane were dried over
CaH2.
reaction mixture was stirred for 17 h at –60 °C, and then the cool-
ing bath was removed. After reaching r.t. (30 min), the reaction was
quenched by the addition of saturated aqueous NH4Cl (10 mL)
and then partitioned between water and EtOAc. The aqueous
phase was then extracted with EtOAc (3ϫ10 mL). The combined
organic extracts were washed with brine, dried with MgSO4, and
filtered, and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography (silica gel,
n-hexane, then n-hexane/EtOAc, 2:1) to yield compound 7 (35 mg,
0.14 mmol, 74%). The spectroscopic data were consistent with
those previously reported.[11]
Synthesis of 4: To a solution of 3 (5.40 g, 38.5 mmol, 1 equiv.) in
dry THF (50 mL, 0.15 m) were added allyl nosylamide[3a] (9.40 g,
38.5 mmol, 1 equiv.) and PPh3 (25.3 g, 96.3 mmol, 2.5 equiv.), and
the mixture was cooled to 0 °C. To this solution was added DIAD
(15.0 mL, 77.0 mmol, 2 equiv.) dropwise, and the reaction mixture
was stirred for 18 h until the disappearance of 3 was indicated by
TLC. The solvent was removed under reduced pressure, and the
crude product dissolved in cold Et2O to precipitate the tri-
phenylphosphane oxide. The suspension was filtered, and the sol-
vent was evaporated. The crude product was purified by column
chromatography (silica gel, n-hexane/EtOAc, 5:1Ǟ2:1) to yield
compound 4 (13.9 g, 37.7 mmol, 98%) as light yellow crystals; m.p.
66 °C. Rf = 0.23 (n-hexane/EtOAc, 2:1). [α]2D0 = +116 (c = 0.55,
CHCl3). 1H NMR (400 MHz, [D6]DMSO): δ = 2.00 (s, 3 H), 2.13–
2.17 (m, 2 H), 3.73 (dd, J = 6.0, 1.7 Hz, 2 H), 5.03–5.14 (m, 2 H),
Synthesis of 8: To a solution of 7 (1.76 g, 6.95 mmol, 1 equiv.) in
dry THF (50 mL, 0.15 m) were added propargyl nosylamide[16]
(1.56 g, 6.95 mmol, 1 equiv.) and PPh3 (4.56 g, 17.4 mmol,
2.5 equiv.), and the mixture was cooled to 0 °C and stirred. DIAD
(2.70 mL, 13.9 mmol, 2 equiv.) was added dropwise, and the re-
sulting solution was stirred for 20 h, until the disappearance of 7
was indicated by TLC. The solvent was removed under reduced
pressure, and the crude product was purified by column
chromatography (silica gel, c-hexane/MTBE, 4:1) to yield 8 (2.71 g,
5.70 mmol,82%)asalightyellowoil;Rf=0.35(n-hexane/EtOAc,3:1).
[α]2D0 = –82 (c = 0.32, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
5.26–5.32 (m, 1 H), 5.64–5.69 (m, 1 H), 5.73 (tdd, J = 17.3, 10.2, 1.44 (s, 9 H), 2.11–2.13 (br. s, 1 H), 2.41–2.49 (m, 1 H), 2.59–2.70
5.9 Hz, 1 H), 5.92 (dq, J = 5.8, 1.0 Hz, 1 H), 6.01 (dt, J = 5.6, (m, 1 H), 3.10–3.52 (m, 3 H), 3.64–3.72 (m, 1 H), 3.75–4.33 (m, 4
2.1 Hz, 1 H), 7.62–7.73 (m, 3 H), 8.03–8.06 (m, 1 H) ppm. 13C H), 5.07–5.17 (m, 2 H), 5.60–5.68 (m, 1 H), 5.73–5.77 (m, 1 H),
NMR (100 MHz, [D6]DMSO): δ = 21.1, 35.4, 46.8, 63.5, 78.3, 5.78–5.89 (m, 1 H), 7.60–7.79 (m, 3 H), 7.98–8.03 (m, 1 H) ppm.
118.0, 124.2, 131.3, 131.6, 133.7, 134.3, 134.8, 136.5, 147.9, 13C NMR (100 MHz, CDCl3): δ = 28.8, 37.2, 48.7, 50.7, 60.1, 74.5,
170.9 ppm. IR (neat): ν = 3093, 2940, 1733, 1590, 1543, 1439 cm–1.
77.6, 80.3, 116.2, 124.4, 130.8, 131.2, 131.4, 131.9, 132.8, 134.0,
˜
HRMS (EI): calcd. for C14H15N2O5S [M – Ac] 323.0702; found
323.0700. C16H18N2O6S (366.39): calcd. C 52.45, H 4.95, N 7.65;
found C 52.16, H 5.27, N 7.78.
135.7, 148.8, 155.6 ppm. IR (neat): ν = 3288, 2981, 1686, 1546,
˜
1455, 1439, 1407, 1366, 1265, 1253, 1166, 1120, 1107, 1096, 1060,
1040, 1029, 999, 910, 852, 773, 723 cm–1. HRMS (ESI): calcd. for
C23H30N3O6SNa [M
+
Na]+ 476.1855; found 476.1862.
Synthesis of 5: To a solution of 4 (11.9 g, 32.5 mmol, 1 equiv.) in
THF (160 mL, 0.2 m) were added K2CO3 (13.5 g, 97.4 mmol,
3 equiv.) and thiophenol (3.30 mL, 32.5 mmol, 1 equiv.), and the
suspension was heated to 70 °C for 3.5 h. The reaction mixture was
allowed to reach r.t. and then was partitioned between brine and
methyl tert-butyl ether (MTBE). The aqueous phase was then ex-
tracted with MTBE (6ϫ50 mL), and the combined organic ex-
tracts were dried with Na2SO4 and filtered. The solvent was re-
moved under reduced pressure. The crude product was dissolved in
methanol (8 mL), and the resulting solution was treated with
Boc2O (7.09 g, 32.5 mmol, 1 equiv.). The reaction mixture was
heated to 60 °C for 12 h, and then the solvent was removed under
reduced pressure. The crude product was passed through a short
pad of silica (MTBE). The crude product was dissolved in meth-
anol (400 mL), and KCN (50 mg) was added. The reaction mixture
was stirred for 12 h at room temp. The solvent was evaporated, and
the residue was partitioned between water and EtOAc. The aque-
ous phase was then extracted with EtOAc (6ϫ50 mL). The com-
bined organic extracts were washed with brine, dried with MgSO4,
and filtered, and the solvent was removed under reduced pressure.
The crude product was purified by column chromatography (silica
gel, n-hexane/EtOAc, 4:1) to yield compound 5 (7.64 g, 27.6 mmol,
85% over three steps) as a colorless oil. The spectroscopic data
were consistent with those previously reported.[11]
C20H32N2O5 (380.48): calcd. C 58.09, H 6.15, N 8.84; found C
57.91, H 6.06, N 8.68.
Synthesis of 9: A solution of 8 (200 mg, 0.42 mmol) in dry DCM
(3 mL, 0.15 m) was cooled to –10 °C and then saturated with ethyl-
ene for 20 min. A solution of catalyst 16 (13 mg, 5 mol-%) in dry
DCM (1 mL) was added, and the reaction mixture was stirred for
24 h at 45 °C. The solvent was removed under reduced pressure,
and the crude product was purified by column chromatography
(silica gel, c-hexane/MTBE, 4:1) to yield 9 (166 mg, 0.35 mmol,
83%) as a colorless foam; m.p. 59–60 °C. Rf = 0.35 (n-hexane/
EtOAc, 3:1). [α]2D0 = +5 (c = 0.10, CHCl3). 1H NMR (500 MHz,
[D6]DMSO, 75 °C): δ = 1.45 (s, 9 H, 15-H), 2.31 (s, 2 H, 7-H), 2.67
(s, 1 H, 4-H), 3.03–3.05 (m, 1 H, 5-Ha), 3.46–3.53 (m, 2 H, 5-Hb
+ 10-Ha), 3.84–4.04 (m, 2 H, 1-H), 4.10–4.22 (m, 1 H, 6-H), 4.25–
4.29 (m, 1 H, 10-Hb), 5.12 (d, J = 10.9 Hz, 12-Hcis), 5.20 (d, J =
17.8 Hz, 12-Htrans), 5.72–5.80 (m, 2 H, 8-H, 9-H), 5.89 (s, 1 H, 3-
H), 6.36 (dd, J = 17.8, 10.9 Hz, 11-H), 7.86–7.98 (m, 3 H, Ar),
8.05–8.06 (m, 1 H, Ar) ppm. 13C NMR (125 MHz, [D6]DMSO,
75 °C): δ = 25.9 (+, C-15), 28.6 (–, C-7), 36.7 (–, C-4), 44.6 (+, C-
1), 45.8 (+, C-5), 50.4 (–, C-6), 79.8 (+, C-14), 113.1 (+, C-12),
123.0 (–, C-9), 124.6 (–, C-8), 124.8 (–, C-Ar), 128.5 (–, C-3), 130.6
(–, C-Ar), 132.8 (–, C-Ar), 133.6 (+, C-2), 135.2 (–, C-Ar), 136.6
(–, C-11), 154.5 (+, C-13) ppm. IR (neat): ν = 2977, 2931, 1726,
˜
1688, 1546, 1456, 1409, 1370, 1364, 1256, 1237, 1168, 1126,
1112 cm–1. HRMS (ESI): calcd. for C19H21N3O6S [M – C4H8]
419.1151; found 419.1158. C20H32N2O5 (380.48): calcd. C 58.09, H
6.15, N 8.84; found C 58.77, H 6.49, N 8.61.
Synthesis of 7: A solution of nBuLi (0.26 mmol, 1.1 equiv.) in THF
(1.3 mL) was prepared, and the resulting mixture was cooled to
–100 °C. To this solution was added compound 6 (127 mg,
0.23 mmol, 1 equiv.) in dry THF (1 mL) over 5 min by using a sy-
ringe pump and dripping the solution past the cold wall of the
flask to achieve precooling. After addition, the solution was stirred
for 30 min, and the temperature was slowly raised to –60 °C. The
Synthesis of 11 through Tandem Metathesis/Oxidation: Compound
8 (100 mg, 0.21 mmol, 1 equiv.) was transformed into 9 following
the procedure described above. The solvent was removed under re-
Eur. J. Org. Chem. 2013, 1346–1355
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1351

S. Kress, J. Weckesser, S. R. Schulz, S. Blechert
FULL PAPER
duced pressure to obtain the crude product, which was dissolved
mixture. The excess amount of diazomethane was destroyed with
acetic acid, and the reaction was quenched with water. The aqueous
phase was extracted with DCM (3ϫ15 mL). The combined organic
extracts were dried with Na2SO4 and filtered, and the solvent was
removed under reduced pressure. The crude product was purified
by column chromatography (silica gel, n-hexane/EtOAc, 3:1) to
yield 12 (300 mg, 0.59 mmol, 91%) as a colorless foam. Rf = 0.49
(n-hexane/EtOAc, 2:1). 1H NMR (500 MHz, [D6]DMSO, 65 °C): δ
[18]
in MeCN/EtOAc (1:1 v/v, 3 mL). After NaIO4/SiO2
(0.5 g,
0.46 mmol, 2.2 equiv.) was added, the suspension was stirred for
24 h at room temp. The reaction mixture was filtered, and the sol-
vent was removed under reduced pressure. The crude product was
purified by column chromatography (silica gel, c-hexane/MTBE,
3:1) to yield 11 (33 mg, 69 μmol, 33%, 42% brsm 9) as a colorless
foam; m.p. 70–71 °C. Rf = 0.25 (n-hexane/EtOAc, 2:1). [α]2D0 = –20
(c = 0.3, CHCl3). 1H NMR (500 MHz, [D6]DMSO, 95 °C): δ = = 1.46 (s, 9 H, 15-H), 2.22–2.36 (m, 2 H, 7-H), 2.70 (br. s, 1 H, 4-
1.42 (s, 9 H), 2.33–2.37 (m, 2 H), 2.81–2.88 (m, 1 H), 3.08 (dd, J
= 12.9, 8.3 Hz), 3.50–3.55 (m, 1 H), 3.56 (dd, J = 12.9, 5.3 Hz, 1
H), 3.83 (dt, J = 16.9, 2.5 Hz, 1 H), 4.05 (d, J = 16.9 Hz, 1 H),
4.20–4.23 (m, 1 H), 4.23–4.27 (m, 1 H), 5.72–5.81 (m, 2 H), 6.97–
7.00 (m, 1 H), 7.82–7.86 (m, 1 H), 7.87–7.89 (m, 2 H), 7.97–8.01
H), 3.07 (m, 1 H, 5-Ha), 3.24–3-26 (m, 1 H, 5-Hb), 3.53 (m, 1 H,
10-Ha), 3.75 (s, 3 H, 12-H), 3.82–3.95 (m, 2 H, 1-H), 4.21 (m, 1 H,
6-H), 4.28 (m, 1 H, 10-Hb), 5.74–5.84 (m, 2 H, 8-H, 9-H), 6.86 (m,
1 H, 3-H), 8.08 (m, 2 H, Ar), 8.44 (m, 2 H, Ar) ppm. 13C NMR
(125 MHz, [D6]DMSO, 65 °C): δ = 26.2 (+, C-7), 28.6 (–, C-15),
(m, 1 H), 9.48 (s, 1 H) ppm. 13C NMR (125 MHz, [D6]DMSO, 37.1 (–, C-4), 40.8 (–, C-10), 44.4 (+, C-1), 44.8 (+, C-5), 49.9 (–,
95 °C): δ = 25.6, 28.1, 37.8, 40.3, 42.2, 45.0, 49.6, 79.6, 122.5, 124.2, 49.9), 52.4 (–, C-12), 80.0 (+, C-14), 123.1 + 124.7 (–, C-8, C-9),
124.4, 130.2, 130.4, 132.3, 134.8, 137.6, 147.8, 148.0, 154.1, 125.3 (–, C-Ar), 128.0 (+, C-2), 129.4 (–, C-Ar), 138.5 (–, C-3),
191.6 ppm. IR (neat): ν = 2965, 2925, 2852, 1686, 1590, 1546, 1476,
142.7 (+, Arq), 150.8 (+, Arq), 154.5 (+, C-13), 164.9 (+, C-
˜
1456, 1439, 1408, 1391, 1369, 1310, 1293, 1259, 1231, 1167, 1126,
11) ppm. IR (neat): ν = 3503, 3105, 3068, 3039, 2976, 2955, 2933,
2852, 1716, 1690, 1661, 1606, 1590, 1532, 1478, 1456, 1437, 1408,
˜
1117, 1087, 1060, 1031, 999 cm–1. HRMS (EI): calcd. for
C18H18N3O6S [M – OtBu] 404.0910; found 404.0912. C20H32N2O5 1392, 1352, 1311, 1268, 1234, 1218, 1170, 1112, 1089, 1070, 1034,
(380.48): calcd. C 55.33, H 5.70, N 8.80; found C 55.14, H 5.98, N
8.28.
1013 cm–1. HRMS (ESI): calcd. for C23H29N3O8S [M + H]
508.1748; found 508.1743.
Synthesis of 10: A solution of AD-mix-β (2.13 g) in tert-butyl Synthesis of 13: To a suspension of 12 (10 mg, 20 μmol, 1 equiv.)
alcohol/H2O (1:1 v/v, 40 mL) was stirred for 15 min at 0 °C. Com-
pound 9 (600 mg, 1.26 mmol) was added, and the solution was
stirred for 24 h at 0 °C. NaSO3 was added, and the reaction mixture
was stirred for 1 h at room temp. The resulting solution was parti-
tioned between water and EtOAc, and the aqueous phase was ex-
tracted with EtOAc (3ϫ15 mL). The aqueous phase was saturated
with NaCl, and the resulting solution was extracted with EtOAc
(3ϫ15 mL). The combined organic extracts were dried with
MgSO4 and filtered, and the solvent was removed under reduced
pressure. The crude product was purified by column chromatog-
raphy (silica gel, DCM then DCM/MeOH, 1:1) to yield 10 (307 mg,
0.60 mmol, 48%, 87% brsm) as a white foam; m.p. 75–80 °C. Rf =
0.65 (DCM/MeOH, 9:1). [α]2D0 = +8.5 (c = 0.23, CHCl3). 1H NMR
(400 MHz, [D6]DMSO): δ = 1.41 (s, 9 H), 2.03 (br. s, 2 H), 2.21–
2.27 (m, 2 H), 3.36–3.51 (m, 4 H), 3.63–3.86 (m, 1 H), 3.94–4.01
(m, 2 H), 4.01–4.17 (m, 2 H), 4.62–5.08 (m, 2 H), 4.62–5.08 (m, 3
H), 7.78–7.91 (m, 3 H), 7.92–7.99 (m, 1 H) ppm. 13C NMR
and K2CO3 (28 mg, 0.2 mmol, 10 equiv.) in MeCN/DMSO (98:2 v/
v, 1 mL) was added thiophenol (10 μL, 99 μmol, 5 equiv.), and the
reaction mixture was stirred at room temp. for 5 h, until the disap-
pearance of 12 was indicated by TLC (closed vessel). The reaction
was quenched by the addition of water (10 mL), and the aqueous
phase was extracted with DCM (5ϫ10 mL). The combined organic
extracts were dried with Na2SO4, and filtered, and the solvent was
removed under reduced pressure. The crude product (19 mg) was
purified by column chromatography [n-hexane/EtOAc (2:1) then
DCM/MeOH (9:1)] to yield compound 13 (5 mg, 83 μmol, 78%)
as a colorless oil. Rf = 0.53 (DCM/MeOH, 9:1). 1H NMR
(500 MHz, [D6]DMSO, 65 °C): δ = 2.24–2.35 (m, 2 H, 7-H), 2.45
(br. s, 1 H, 4-H), 2.56–2.78 (m, 2 H, 5-H), 3.42 (s, 2 H, 1-H), 3.47–
3.55 (m, 1 H, 10-Ha), 3.72 (s, 3 H, 12-H), 3.72 (s, 3 H, 12-H), 4.18
(s, 1 H, 6-H), 4.20–4.26 (m, 1 H, 10-Hb), 5.72–5.87 (m, 2 H, 8-H,
9-H), 6.83–6.87 (m, 1 H, 3-H) ppm. 13C NMR (125 MHz, [D6]-
DMSO, 65 °C): δ = 26.4 (+, C-7), 28.6 (–, C-15), 36.2 (–, C-4), 40.6
(100 MHz, [D6]DMSO): δ = 27.2, 29.8, 35.0, 43.5, 45.9, 46.2, 53.9, (–, C-10), 2ϫ44.6 (+, C-1, C-5), 50.3 (C-6), 51.7 (–, C-12), 79.5 (+,
69.8, 70.0, 75.9, 121.2, 124.9, 125.9, 127.0, 131.2, 131.9, 133.1, C-14), 123.0 + 124.4 (–, C-8, C-9), 132.3 (+, C-2), 139.1 (–, C-3),
134.2, 136.9, 145.3, 153.2 ppm. IR (neat): ν = 3426, 2975, 2928, 166.3 (C-11) ppm. HRMS (ESI): calcd. for C17H27N2O4 [M + H]+
˜
2852, 1686, 1546, 1455, 1413, 1366, 1299, 1249, 1165, 1126, 1074,
1060, 1035 cm–1. HRMS (EI): calcd. for C23H31N3O6S 509.1832;
found 509.1888. C20H32N2O5 (380.48): calcd. C 54.21, H 6.13, N
8.25; found C 54.70, H 6.46, N 8.17.
323.1965; found 323.1975.
Synthesis of 17: DIBAL-H (0.012 m in toluene, 0.1 mL, 12 μmol,
1.3 equiv.) was added to a solution of aldehyde 11 (4.3 mg,
9.0 μmol, 1 equiv.) in dry THF (1 mL, 0.01 m) at –78 °C. After stir-
ring the solution for 30 min, the mixture was allowed to reach r.t.
and was then stirred for an additional 15 min. The reaction was
quenched by the slow addition of a saturated Rochel salt solution
(5 mL), and the resulting solution was extracted with DCM
(3ϫ10 mL). The collected organic layers were dried with Na2SO4
and filtered, and the solvent was removed under reduced pressure.
The crude product was purified by column chromatography (silica
gel, c-hexane/MTBE, 3:1) to yield compound 17 (4.0 mg, 8.3 μmol,
92%) as a colorless foam. Single crystals suitable for X-ray diffrac-
tion were obtained by vapor diffusion (MeCN/Et2O). Rf = 0.38 (n-
hexane/EtOAc, 1:1). 1H NMR (500 MHz, CD3OD, –10 °C): δ =
1.51 + 1.55 (s, 9 H, 18-H), 2.22–2.39 (m, 2 H, 7-H), 2.57–2.65 (m,
1 H, 4-H), 2.67–2.79 (m, 0.6 H, 5-H), 2.88–3.02 (m, 0.4 H, 5-H),
3.06–3.18 (m, 0.4 H, 5-H), 3.20–3.30 (m, 0.6 H, 5-H), 3.44–3.74
(m, 2.4 H, 1-H, 10-H), 3.86–3.96 (m, 0.6 H, 1-H), 3.99 (br. s, 2 H,
Synthesis of 12: To a solution of aldehyde 11 (311 mg, 0.65 mmol,
1 equiv.) in MeCN (7 mL) were added at 0 °C NaH2PO4 buffer
(2.67 m aqueous solution, 6.5 mL), H2O2 (30wt.-% in H2O,
0.13 mL, 2 equiv.), and NaClO2 (89 mg, 0.98 mmol, 1.5 equiv.) dis-
solved in H2O (0.5 mL). After 5 min, the ice bath was removed,
and the reaction mixture was stirred for 45 min, until the disap-
pearance of 11 was indicated by TLC. The reaction was quenched
by the addition of aqueous Na2S2O5 (1.0 m solution, 0.5 mL) and
water (15 mL). The aqueous phase was extracted with DCM
(3ϫ15 mL). The combined organic extracts were dried with
Na2SO4 and filtered, and the solvent was removed under reduced
pressure. The crude product was dissolved in DCM (5 mL), and
the resulting solution was titrated with diazomethane (1 m in Et2O),
until full esterification was indicated by a yellow color that was
caused by the presence of unreacted diazomethane in the reaction
1352
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1346–1355

Total Syntheses of Dipiperidine Alkaloids
15-H), 4.13–4.20 (m, 0.4 H, 6-H), 4.27–4.33 (m, 0.6 H, 6-H), 4.33– 2902, 2871, 2857, 1691, 1661, 1606, 1597, 1477, 1454, 1408, 1390,
4.50 (m, 1 H, 10-H), 5.72 (s, 1 H, 3-H), 5.74–5.90 (m, 2 H, 8-H, 9-
1365, 1304, 1257, 1251, 1230, 1171, 1130, 1108, 1088, 1057,
H), 8.06–8.10 (m, 2 H, 12-H), 8.47–8.51 (m, 2 H, 13-H) ppm. 13C 1031 cm–1. HRMS (ESI): calcd. for C20H35N2O4 [M + H]+
NMR (125 MHz, CD3OD, –10 °C): δ = 25.0 + 25.3 (+, C-7), 27.2
(–, C-18), 34.2 + 34.8 (–, C-4), 39.2 + 40.4 (+, C-10), 44.9 (+, C-
5), 45.2 (+, C-1), 49.5 + 51.0 (–, C-6), 63.2 (+, C-15), 80.3 (+, C-
17), 121.4 (–, C-3), 122.7 (–, C-8), 123.5 (–, C-9), 124.0 (–, C-Ar),
128.8 (–, C-Ar), 135.8 (+, C-2), 140.1 (+, C-11), 150.3 (+, C-14),
367.2591; found 367.2587.
Synthesis of 20: To a solution of 19 (66 mg, 0.18 mmol, 1 equiv.) in
DCM (21 mL) were added successively pyridine (117 μL,
1.40 mmol, 8 equiv.) and trifluoroacetic anhydride (100 μL,
0.72 mmol, 4 equiv.) at 0 °C. After 15 min, the ice bath was re-
moved, and the solution was stirred for an additional 45 min. The
reaction was quenched by the addition of water (20 mL), and the
resulting solution was extracted with DCM (3ϫ20 mL). The com-
bined organic extracts were dried with Na2SO4 and filtered, and
the solvent was removed under reduced pressure. The crude prod-
uct was placed under high vacuum (7ϫ10–5 mbar) for 2 h to obtain
compound 20 (83 mg, 0.18 mmol, 99%) as a colorless oil. The
product was obtained as a complex mixture of rotamers, and, there-
fore, the NMR spectroscopic data could not be analyzed. Rf = 0.59
155.1 (+, C-16) ppm. IR (neat): ν = 3440, 3105, 3067, 3038, 2975,
˜
2931, 2855, 1688, 1654, 1606, 1591, 1531, 1477, 1457, 1410, 1392,
1351, 1312, 1289, 1252, 1232, 1219, 1166, 1112, 1092, 1031,
1012 cm–1. HRMS (ESI): calcd. for C22H29N3O7SNa [M + Na]+
502.1618; found 502.1613.
Synthesis of 18: To a solution of 17 (50 mg, 0.1 mmol, 1 equiv.)
in DCM (2.0 mL) were added ethyl vinyl ether (30 μL, 0.3 mmol,
3 equiv.) and PPTS (5.0 mg, 21 μmol, 0.2 equiv.) at room temp.,
and the solution was stirred for 12 h. The reaction mixture was
quenched by the addition of a saturated NaHCO3 solution
(10 mL), and the aqueous phase was extracted with DCM
(3ϫ10 mL). The combined organic extracts were dried with
Na2SO4 and filtered, and the solvent was removed under reduced
pressure. The crude product was purified by flash column
chromatography (silica gel, n-hexane/EtOAc, 1:1) to obtain com-
pound 18 (53 mg, 96 μmol, 96%) as a colorless oil. Rf = 0.70 (n-
hexane/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3): δ = 1.17 (t, J =
7.2 Hz, 3 H, 15-H), 1.26 (d, J = 5.4 Hz, 3 H, 13-H), 1.47 (s, 9 H,
18-H), 2.05–2.40 (m, 2 H, 7-H), 2.50–2.76 (m, 1 H, 4-H), 3.40–3.65
(m, 3 H, 5-Ha, 14-H), 3.84–3.98 (m, 2 H, 11-H), 4.11 (mc, 1 H, 6-
H), 4.16–4.33 (br. m, 1 H, 5b-H), 4.64 (q, J = 5.4 Hz, 1 H, 12-H),
5.60 (br. s, 1 H, 3-H), 5.64–5.74 (m, 2 H, 8-H, 9-H), 7.92–7.96 (m,
2 H, Ar), 8.28–8.37 (m, 2 H, Ar) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.0 (–, C-15), 20.0 (–, C-13), 25.4 (C-7), 28.7 (–, C-
18), 36.0 (C-4), 40.8 (C-5), 45.8, 46.1, 49.3 (C-6), 61.2 (+, C-14),
67.0 (+, C-11), 80.5 (+, C-17), 99.6 (–, C-12), 122.8, 124.4 (C-3),
129.1 (–, C-Ar), 133.1 (+, C-Arq), 150.5 (+, C-Arq) ppm. IR (neat):
(c-hexane/EtOAc, 2:1). IR (neat): ν = 3040, 2976, 2929, 2900, 2857,
˜
1692, 1456, 1406, 1390, 1365, 1355, 1308, 1286, 1257, 1246, 1203,
1163, 1136, 1108, 1085, 1054, 1029, 987 cm–1. HRMS (ESI): calcd.
for C22H33F3N2O5Na [M + Na]+ 485.2234; found 485.2218.
Synthesis of 21: To a solution of 20 (154 mg, 0.33 mmol, 1 equiv.)
in acetone (50 mL) was added HCl (0.5 m solution, 0.1 mL) at
room temp., and the reaction mixture was stirred for 2 h, until the
disappearance of 20 was indicated by TLC. The mixture was con-
centrated to 5 mL, and water (15 mL) and DCM (15 mL) were
added. The aqueous phase was extracted with DCM (3ϫ15 mL),
and the combined organic extracts were dried with Na2SO4 and
filtered. The solvent was removed under reduced pressure. The re-
sulting crude product (131 mg) was used without further purifica-
tion in the next step. The product was obtained as a complex mix-
ture of rotamers, and, therefore, the NMR spectroscopic data could
not be analyzed. Rf = 0.27 (n-hexane/EtOAc, 1:1). HRMS (ESI):
calcd. for C18H25F3N2O4Na [M + Na] 413.1659; found 413.1658.
ν = 3452, 3105, 3066, 3038, 2978, 2933, 2900, 2871, 1689, 1606,
˜
Synthesis of 23: To a solution of crude product 21 (131 mg,
0.33 mmol, 1 equiv.) in EtOAc (100 mL) was added PtO2 (Adam’s
catalyst, 76 mg, 1 equiv.). The suspension was vigorously stirred at
room temp. under an atmosphere of H2 (balloon) for 16 h. The
catalyst was filtered, and the solvent was removed under reduced
pressure. The crude product (130 mg) was dissolved in dry DCM
1588, 1532, 1478, 1456, 1408, 1390, 1351, 1312, 1288, 1252, 1233,
1219, 1168, 1110, 1091, 1057, 1043, 1030, 1013, 988 cm–1. HRMS
(ESI): calcd. for C26H37N3O8SNa [M + Na] 574.2194; found
574.2206.
Synthesis of 19: To a suspension of 18 (50 mg, 91 μmol, 1 equiv.)
and Cs2CO3 (295 mg, 0.91 mmol, 10 equiv.) in MeCN/DMSO (98:2 (35 mL), and the resulting solution was treated with PCC (142 mg,
v/v, 3.5 mL) was added thiophenol (47 μL, 0.45 mmol, 5 equiv.),
and the reaction mixture was stirred at 70 °C for 2.5 h, until the
disappearance of 18 was indicated by TLC. The reaction was
quenched by the addition of water (15 mL), and the aqueous phase
was extracted with DCM (5ϫ15 mL). The combined organic ex-
tracts were dried with Na2SO4 and filtered, and the solvent was
removed under reduced pressure. The crude product (64 mg) was
purified by column chromatography (EtOAc then DCM/MeOH,
0.67 mmol, 2 equiv.). The reaction was stirred for 90 min. The mix-
ture was concentrated to 2 mL, and Et2O (30 mL) was added
through a syringe to precipitate the inorganic compounds. The sus-
pension was filtered, and the residue was washed with Et2O
(5ϫ10 mL). The combined organic phases were filtered through a
pad of Celite®, and the solvent was removed under reduced pres-
sure. The crude aldehyde (126 mg) was used without further purifi-
cation in the next step. The oxidation and esterification were per-
formed according to the procedure described for 12. The resulting
9:1) to yield compound 19 (31 mg, 83 μmol, 92%) as a colorless
1
oil. Rf = 0.55 (DCM/MeOH, 9:1). H NMR (400 MHz, CDCl3): δ crude product 22 (112 mg) was used without further purification
= 1.18 (t, J = 7.2 Hz, 3 H, 15-H), 1.28 (d, J = 5.0 Hz, 3 H, 13-H),
in the next step. To a solution of crude methyl ester 22 (75 mg,
1.45 (s, 9 H, 18-H), 2.16–2.42 (m, 3 H, 4-H, 5-H), 2.68–2.85 (m, 2 0.18 mmol, 1 equiv.) dissolved in dry DCM/MeOH (5:1 v/v, 25 mL)
H, 1-H), 3.32–3.66 (m, 5 H, 17-H, 14-H, NH), 3.81–3.97 (m, 3 H, was added freshly activated and ground MS (3 Å, 1.5 g), and the
6-H, 10-H), 2.16–2.42 (m, 3 H, 4-H, 5-H), 4.63–4.72 (m, 1 H, 12- resulting suspension was stirred for 30 min at room temp. MeONa
H), 5.57–5.69 (m, 2 H, 8-H, 9-H), 5.72 (br. s, 1 H, 3-H) ppm. 13C
(486 mg, 9.0 mmol, 50 equiv.) was added, and the reaction mixture
NMR (100 MHz, CDCl3): δ = 15.6 (–, C-15), 20.1 + 20.2 (–, C- was stirred for 18 h at room temp. The solids were removed by
13), 26.2 (+, C-5), 28.8 (–, C-18), 33.9 (–, C-4), 40.1 + 41.1 (+, C- filtration, and the resulting solution was partitioned between H2O
10), 44.3 + 44.9 (+, C-1), 45.4 + 46.1 (+, C-7), 49.8 + 51.2 (–, C- and DCM. The aqueous phase was then extracted with DCM
6), 61.0 + 61.3 (–, C-14), 67.7 (+, C-11), 99.3 + 99.5 (–, C-12),
112.1 (–, C-9), 123.5 (–, C-8), 124.4 (–, C-3), 136.4 + 137.2 (+, C-
(3ϫ20 mL). The combined organic extracts were dried with
Na2SO4 and filtered, and the solvent was removed under reduced
pressure. The crude product was purified by column chromatog-
2), 156.0 (+, C-16) ppm. IR (neat): ν = 3338, 3037, 2975, 2930,
˜
Eur. J. Org. Chem. 2013, 1346–1355
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1353

S. Kress, J. Weckesser, S. R. Schulz, S. Blechert
FULL PAPER
raphy (silica gel, EtOAc then DCM/MeOH, 9:1) to yield compound
(+, C-14), 135.2 (–, C-13), 173.5 (+, C-15) ppm. IR (neat): ν =
˜
23 as a single diastereomer (24 mg, 74 μmol, 41%) as a colorless
oil. Rf = 0.42 (DCM/MeOH, 9:1). H NMR (400 MHz, CDCl3): δ 2517, 2484, 2458, 2408, 2351, 2129, 1738, 1643, 1627, 1605, 2586,
3401, 3180, 3079, 2995, 2929, 2860, 2785, 2762, 2727, 2694, 2568,
1
= 1.11–1.65 (m, 7 H, 3-Ha, 7-Ha, 8-H, 9-H), 1.43 (s, 9 H, 15-H),
1.71–1.84 (m, 1 H, 7-Hb), 2.08–2.25 (m, 2 H, 2-H, 3-Hb), 2.25–
2.45 (br. m, 1 H, 1-Ha), 2.61–2.85 (m, 2 H, 4-H, 5-Ha), 3.04 (d, J
= 12.0 Hz, 1 H, 1-Hb), 3.41 (d, J = 10.2 Hz, 1 H, 5-Hb), 3.77–4.42
(br. m, 4 H, 6-H, 10-H, NH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 19.4 (+, C-8), 25.7 (+, C-7, C-9), 28.8 (–, C-15), 31.3 (+, C-3),
33.5 (–, C-4), 41.6 (–, C-2), 47.0 (C-5), 47.7 (C-1), 52.3 (C-12), 79.9
(+, C-14), 155.0 (C-13), 173.5 ppm (C-11), (signals for C-6 and C-
10 were not detected) ppm. HRMS (ESI): calcd. for C17H31N2O4
[M + H]+ 327.2278; found 327.2277.
1576, 1537, 1458, 1439, 1409, 1378, 1370, 1345, 1310, 1287, 1250,
1228, 1217, 1201, 1153, 1133, 1106, 1079, 1044, 1022 cm–1. HRMS
(ESI): calcd. for C16H29N2O2 [M + H]+ 281.2224; found 281.2220.
Synthesis of 1·2HCl: A solution of methyl ester 25 (7.0 mg,
20 μmol, 1equiv.) in HCl (0.5 m solution, 1 mL) was heated to 80 °C
and then stirred for 15 h, until the disappearance of 25 was indi-
cated by HPLC-ESI. The solvent was removed under reduced pres-
sure, and the residue was placed under high vacuum
(1.3ϫ10–5 mbar) for 2 h. The residue was dissolved in MeOH, and
the solution was filtered through
a syringe-filter (pore size
Synthesis of 24: To a solution of 23 (10 mg, 31 μmol, 1 equiv.) in
MeCN (10 mL), which were divided into 10 vessels (each 1 mL),
were successively added K2CO3 (10ϫ4.0 mg, 0.31 mmol, 10 equiv.)
and 4-bromobut-1-ene (10ϫ2.9 mg, 0.21 mmol, 7 equiv.). The ves-
sels were closed, and the reaction mixtures were stirred at 80 °C for
17 h. Water was added to the combined reaction mixtures, and the
resulting mixture was partitioned between H2O and DCM. The
aqueous phase was then extracted with DCM (3ϫ10 mL). The
combined organic extracts were dried with Na2SO4 and filtered,
and the solvent was removed under reduced pressure. The crude
product was purified by column chromatography [silica gel, n-hex-
ane/EtOAc (5:1) then EtOAc] to yield compound 24 (9.8 mg,
26 μmol, 84%) as a colorless oil. Rf = 0.38 (EtOAc). 1H NMR
(500 MHz, CDCl3): δ = 1.08–1.14 (m, 1 H, 3-Ha), 1.32–1.68 (m, 4
H, 8-H, 7-Ha, 9-Ha), 1.49 (s, 9 H, 19-H), 1.80–1.90 (m, 2 H, 5-Ha,
7-Hb), 2.04–2.16 (m, 2 H, 1-Ha, 3-Hb), 2.19–2.29 (m, 1 H, 4-H),
2.30–2.38 (m, 2 H, 12-H), 2.53–2.65 (m, 2 H, 11-H), 2.72 (dd, J =
12.1, 3.9 Hz, 1 H, 2-H), 2.77–2.93 (br. m, 2 H, 5-Hb, 10-Ha), 3.26–
3.27 (m, 1 H, 1-Hb), 2.30–2.38 (m, 2 H, 12-H), 3.72 (s, 3 H, 16-
H), 3.87–3.97 (br. m, 1 H, 6-H), 3.97–4.10 (br. m, 1 H, 10-Hb),
5.05 (dt, J = 10.1, 1.3 Hz, 1 H, 14-Hcis), 5.11 (dt, J = 17.1, 1.6 Hz,
1 H, 14-Htrans), 5.83 (ddt, J = 17.0, 10.1, 6.8 Hz, 1 H, 13-H) ppm.
13C NMR (125 MHz, CDCl3): δ = 20.8 (+, C-8), 27.4 (+, C-9),
27.5 (+, C-7), 29.6 (–, C-19), 32.6 (+, C-12), 32.7 (+, C-3), 35.0
(–, C-4), 43.2 (–, C-2), 53.3 (–, C-16), 56.8 (+, C-1), 57.0 (C-6), 58.1
(C-5), 59.8 (+, C-11), 82.0 (+, C-18), 117.7 (+, C-14), 137.7 (–, C-
0.45 μm). Evaporation of the solvent furnished compound 1·2HCl
(6.4 mg, 18.9 μmol, 95%) as a white powder. Single crystals suitable
for X-ray diffraction were obtained by vapor diffusion (Et2O/
MeOH). 1H NMR (700 MHz, CD3OD): δ = 1.53–1.69 (br. m, 3 H,
3-Ha, 7-Ha, 8-Ha), 1.71–1.83 (br. m, 1 H, 9-Ha), 1.92–1.94 (m, 1
H, 9-Hb), 1.98 (br. s, 2 H, 7-Hb, 8-Ha), 2.38–2.40 (m, 1 H, 3-Ha),
2.48 (br. s, 1 H, 4-H), 2.66 (br. s, 2 H, 12-H), 2.96 (br. s, 1 H, 5-
Ha), 3.01–3.16 (m, 3 H, 2-H, 10-Hb, 1-Hb), 3.29 (br. s, 1 H, 6-H),
3.33 (m, 2 H, 11-H), 3.45–3.46 (m, 1 H, 10-Hb), 3.70–3.78 (m, 1
H, 5-Hb), 3.79–3.90 (m, 1 H, 1-Hb), 5.22 (d, J = 10.0 Hz, 1 H, 14-
H
cis), 5.30 (d, J = 17.1 Hz, 1 H, 14-Htrans), 5.81 (m, 1 H, 13-
H) ppm. 13C NMR (175 MHz, CDCl3, CD3OD): δ = 24.1 + 24.1
+ 26.6 (+, C-7) + (+,C-8) + (+,C-9), 28.2 (+, C-3), 30.3 (+, C-12),
38.8 (–, C-4), 40.8 (–, C-2), 48.0 (+, C-10), 54.8 (+, C-1), 55.3 (+,
C-5), 59.0 (+, C-11), 60.4 (–, C-6), 102.2 (+, C-14), 134.5 (–, C-13),
174.1 (+, C-15) ppm. HRMS (ESI): calcd. for C15H27N2O2 [M +
H]+ 267.2067; found 267.2067.
Virgidivarine (1): A solution of dihydrochloride 1·2HCl (5.5 mg,
18.2 μmol, 1 equiv.) in D2O was placed in an NMR tube. To this
solution was added LiOH (0.36 m solution in D2O, 105 μL,
2.1 equiv.). The deprotonation process was finished within seconds,
as indicated by monitoring the reaction by NMR spectroscopy. No
side products were observed during the reaction that furnished
1
compound 1 in quantitative yield. H NMR (700 MHz, CD3OD):
δ = 1.44–1.50 (m, 1 H, 7-Ha), 1.51–1.57 (m, 1 H, 8-Ha), 1.64–1.70
(m, 1 H, 9-Ha), 1.81–1.50 (br. m, 3 H, 4-Ha, 5-Ha, 8-Hb), 1.91–
1.96 (m, 2 H, 7-Hb, 9-Hb), 2.04 (t, J = 11.6 Hz, 1 H, 1-Ha), 2.06–
2.09 (m, 1 H, 3-Hb), 2.33–2.36 (m, 2 H, 12-H), 2.41–2.45 (m, 1 H,
2-H), 2.53–2.55 (m, 2 H, 11-H), 2.91–2.92 (m, 1 H, 6-H), 2.95 (dt,
J = 12.8, 2.6 Hz, 1 H, 10-Ha), 3.04–3.07 (m, 1 H, 5-Hb), 3.21–3.23
(m, 1 H, 1-Hb), signal for 10-Hb is under solvent peak, 5.03 (d, J
= 10.2 Hz, 1 H, 14-Hcis), 5.12 (d, J = 17.1 Hz, 1 H, 14-Htrans), 5.84
(ddt, J = 16.9, 10.2, 6.8 Hz, 1 H, 13-H) ppm. 13C NMR (175 MHz,
CDCl3, CD3OD): δ = 24.8 + 25.1 (+, C-8, C-9), 28.4 (+, C-7), 31.9
(+, C-3), 32.8 (+, C-12), 41.3 (–, C-4), 46.5 (–, C-2), 47.9 (+, C-
10), 57.6 (+, C-5), 58.5 (+, C-1), 60.1 (+, C-11), 62.1 (–, C-6), 117.3
(+, C-14), 138.1 (+, C-13), 182.4 (+, C-15) ppm. HRMS (ESI):
calcd. for C15H27N2O2 [M + H]+ 267.2067; found 267.2067.
13), 157.6 (+, C-17), 175.9 (+, C-15) ppm. IR (neat): ν = 3423,
˜
3359, 3194, 3075, 2953, 2925, 2854, 1735, 1688, 1662, 1632, 1602,
1506, 1468, 1455, 1416, 1391, 1365, 1313, 1259, 1224, 1169, 1089,
1032, 1016 cm–1. HRMS (ESI): calcd. for C21H37O4N2 [M + H]+
381.2753; found 381.2747.
Synthesis of 25: To a solution of 24 (7.0 mg, 18 μmol, 1 equiv.) in
dry methanol (2.5 mL) was added TMSCl (35 μL, 0.28 mmol,
15 equiv.) at 50 °C, and the reaction mixture was stirred for 90 min.
The solvent was removed under reduced pressure, and the residue
placed under high vacuum (1.3ϫ10–5 mbar) for 2 h to furnish com-
pound 25 (6.5 mg, 18.4 μmol, quant.) as a white powder. 1H NMR
(700 MHz, CD3OD): δ = 1.48–1.65 (m, 3 H, 3-Ha, 7-Ha, 8-Ha),
1.70–1.80 (m, 1 H, 9-Ha), 1.91–1.99 (m, 3 H, 7-Hb, 8-Hb, 9-Hb),
2.31–2.36 (m, 2 H, 3-Hb, 4-H), 2.57 (q, J = 7.5 Hz, 2 H, 12-H), Virgiboidine (2): To solution of 1 (5.8 mg, 21 μmol, 1 equiv.) in eth-
2.74 (t, J = 12.7 Hz, 1 H, 5-Ha), 2.90 (t, J = 12.0 Hz, 1 H, 1-Ha), anol (2.5 mL) were added NMM (11 mg, 0.11 μmol, 5 equiv.) and
3.01–3.11 (m, 2 H, 2-H, 10-Ha), 3.12–3.20 (m, 2 H, 11-H), 3.23– EDC (4.6 mg, 24 μmol, 1.1 equiv.). The reaction mixture was
3.24 (m, 1 H, 6-H), 3.45 (d, J = 12.6 Hz, 1 H, 10-Hb), 3.58–3.60 stirred at 25 °C for 10 h, and the solvent was removed under re-
(m, 1 H, 5-Hb), 3.70–3.72 (m, 1 H, 1-Hb), 3.58–3.60 (m, 1 H, 5- duced pressure. The crude product was partitioned between water
Hb), 3.76 (s, 3 H, 16-H), 5.18 (dd, J = 10.2, 0.9 Hz, 1 H, 14-Hcis),
5.26 (dd, J = 17.1, 1.3 Hz, 1 H, 14-Htrans), 5.85 (ddt, J = 17.1, 10.3,
6.1 Hz, 1 H, 13-H) ppm. 13C NMR (175 MHz, CDCl3, CD3OD):
δ = 24.1, (+, C-8), 24.1 (+, C-9), 26.9 (+, C-7), 28.6 (+, C-3), 30.8
(+, C-12), 38.9 (–, C-4), 41.2 (–, C-2), 47.8 (+, C-1), 53.7 (–, C-16),
54.8 (+, C-7), 55.5 (+, C-10), 59.0 (+, C-11), 60.6 (–, C-6), 119.6
and DCM. The organic extract was dried with Na2SO4 and filtered,
and the solvent was evaporated. The product was purified by flash
chromatography (silica gel, EtOAc), which was followed by a solid-
phase extraction (silica C-18, MeOH) to obtain compound 2
(1.5 mg, 6.0 μmol, 29%) as a colorless oil. Rf = 0.19 (EtOAc). H
NMR (700 MHz, CDCl3): δ = 1.38–1.43 (m, 2 H, 2-Ha, 4-Ha),
1
1354
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1346–1355

Total Syntheses of Dipiperidine Alkaloids
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1.55 (br. s, 1 H, 7-Ha, partly covered by water peak), 1.62–1.73 (m,
3 H, 3-Ha, 4-Hb, 7-Hb), 1.84–1.91 (m, 2 H, 2-Hb, 3-Hb), 1.92–
1.96 (m, 1 H, 6-H), 1.99 (dd, J = 11.4, 1.6 Hz, 1 H, 10-Ha), 2.11
(dd, J = 10.6, 2.3 Hz, 1 H, 11-Ha), 2.14–2.23 (m, 2 H, 13-H), 2.24–
2.28 (m, 1 H, 12-Ha), 2.33–2.40 (m, 2 H, 1-Ha, 12-Hb), 2.54–2.58
(m, 1 H, 8-H), 3.04 (d, J = 11.4 Hz, 1 H, 11-Hb), 3.14 (d, J =
10.5 Hz, 1 H, 10-Hb), 3.30 (ddd, J = 11.4, 5.7, 2.1 Hz, 1 H, 5-H),
4.80–4.82 (m, 1 H, 1-Hb), 4.95 (d, J = 10.2 Hz, 1 H, 15-Hcis), 5.02
(dd, J = 17.1, 1.3 Hz, 1 H, 15-Htrans), 5.77 (ddt, J = 17.0, 10.2,
6.7 Hz, 1 H, 14-H) ppm. 13C NMR (175 MHz, CDCl3): δ = 25.3
(+, C-2), 25.7 (+, C-4), 29.1 (+, C-3), 29.6 (+, C-7), 31.5 (+, C-13),
33.0 (–, C-6), 39.8 (–, C-8), 42.7 (+, C-1), 54.9 (+, C-11), 56.9 (+,
C-10), 57.9 (+, C-12), 59.7 (–, C-5), 111.8 (+, C-15), 137.3 (–, C-
14), 171.6 (C-9) ppm. IR (neat): ν = 2925, 2855, 2799, 1637, 1474,
˜
1444, 1355, 1321, 1266, 1154, 1110, 910 cm–1. MS (70 eV): m/z (%)
= 248 [M]+, 207 (100), 164 (1.8), 150 (2.4), 136 (3.2), 124 (13.0),
112 (4.5), 96 (14.8), 84 (36.4), 70 (6.9), 58 (24.4), 41 (13.6). HRMS
(ESI): calcd. for C15H25ON2 [M + H]+ 249.1961; found 249.1963.
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Acknowledgments
We thank Dr. Elisabeth Irran and Paula Nixdorf for the X-ray
analysis and Dr. Sebastian Kemper for his support with the NMR
spectroscopy.
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Published Online: January 17, 2013
Eur. J. Org. Chem. 2013, 1346–1355
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