The biomimetic synthesis and final structure determination of (+)- and (-)-centrolobine, naturally occurring diarylheptanoid 2,6-cis-disubstituted tetrahydro-2H-pyrans

Article abstract of DOI:10.1002/hlca.201000096

The enantiomerically pure title compounds were prepared by oxidative cyclization of their optically active diarylheptanoid precursors. The approach is considered as a biomimetic phenol oxidation via an intermediate quinone methide. The absolute configuration of the precursors is retained, and the transition state adopts the sterically most favorable diequatorial arrangement of the 2,6-substituents to afford the cis-configured natural products. The outcome unambiguously establishes the absolute configurations and the correlation with the chiroptical data. In addition, a problem of regioisomerism that had not been discussed before was solved, and the original assignment of the position of the MeO group in the natural centrolobines could be confirmed. As such the results are the experimental evidence for the corrections of long-term inconsistencies we had postulated in an earlier review article.

Full text of DOI:10.1002/hlca.201000096

Helvetica Chimica Acta – Vol. 93 (2010)
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The Biomimetic Synthesis and Final Structure Determination of
(þ)- and (ꢀ)-Centrolobine, Naturally Occurring Diarylheptanoid
2,6-cis-Disubstituted Tetrahydro-2H-pyrans
by Frank Rogano and Peter Rꢀedi*
Organisch-chemisches Institut der Universitꢀt Zꢁrich, Winterthurerstrasse 190, CH-8057 Zꢁrich
(phone: þ 41-44-8215579; e-mail: peru@oci.uzh.ch)
The enantiomerically pure title compounds were prepared by oxidative cyclization of their optically
active diarylheptanoid precursors. The approach is considered as a biomimetic phenol oxidation via an
intermediate quinone methide. The absolute configuration of the precursors is retained, and the
transition state adopts the sterically most favorable diequatorial arrangement of the 2,6-substituents to
afford the cis-configured natural products. The outcome unambiguously establishes the absolute
configurations and the correlation with the chiroptical data. In addition, a problem of regioisomerism
that had not been discussed before was solved, and the original assignment of the position of the MeO
group in the natural centrolobines could be confirmed. As such the results are the experimental evidence
for the corrections of long-term inconsistencies we had postulated in an earlier review article.
1. Introduction. – 1.1. General. In the course of our investigations concerning the
isolation, synthesis, and biological screening of genuine constituents of African and
Asian Labiatae species of the genera Coleus, Plectranthus, and Solenostemon with
respect to antioxidants, inhibitors of the arachidonate metabolism, and allergens [1 – 3],
we have reported on the isolation, structure elucidation, and partial synthesis of a series
of optically active, oxygenated unbranched long-chain alkylcatechols A and 2,6-cis-
disubstituted tetrahydro-2H-pyrans B from Plectranthus sylvestris [3]. Being consid-
ered to originate from their linear congeners, the tetrahydro-2H-pyrans B were
synthesized by oxidative cyclization of their respective precursors A (Scheme 1) [3][4].
Scheme 1
Since the Plectranthus constituents are closely related to the [n]-gingerols and -diols
A [3], a closer inspection of the current literature was performed. It revealed
significant structural inconsistencies, in particular with respect to the related diaryl-
ꢂ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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heptanoids (curcuminoids) and their cyclic derivatives, the centrolobines (þ)- and (ꢀ)-
1 (Figs. 1 and 2). In a review article covering the chemistry and pharmacology of these
compounds at that time, we disclosed several misinterpretations, and respective
structural revisions were claimed [4] (Fig. 2).
Fig. 1. General overwiev of the title compounds and their isomers and precursors
Fig. 2. Revised structures of the naturally occurring (þ)- and (ꢀ)-centrolobines [4]
1.2. The Centrolobines: A Brief Historical Survey. Since the first isolation and
characterization of (þ)-centrolobine ((þ)-1, [a]D ¼ þ97, Fig. 2), an antibacterially
active constituent from the heartwood of Centrolobium robustum (Leguminosae,
Amazon forest) [5 – 7], considerable confusion concerning the configuration of this
compound and its congeners resulted that persisted until the most recent isolation of
(ꢀ)-centrolobine ((ꢀ)-1, [a]D ¼ ꢀ92.2, Fig. 2) from the stems of Brosimum potabile
(Moraceae, Amazon forest) [8]. The problems originated mainly from the fact that the
compounds occur naturally as both enantiomers [9 – 11], the erroneous assignment of
the absolute configuration of the assumed biogenetic precursor centrolobol [9] and not
reliably identified plant sources [9][10].
1
)
When applying the ꢃbiogeneticꢄ terminology that is based on the diarylheptanoid nomenclature, the
stereogenic C-atoms in the centrolobines are C(3) and C(7). According to the systematic
nomenclature of heterocycles, C(3) becomes C(6), and C(7) becomes C(2) in the tetrahydro-2H-
pyran moieties.

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Meanwhile, the absolute configuration of (ꢀ)-(R)-centrolobol was independently
established [11][12] and the taxonomic problem tackled [10] and settled by [11]2).
Hence, the laevorotatory natural products ((ꢀ)-centrolobine, (ꢀ)-O-demethylcentro-
lobine, and (ꢀ)-centrolobol, Fig. 1) are constituents of Centrolobium paraense, C.
sclerophyllum, and C. tomentosum, whereas the dextrorotatory enantiomers were
isolated from C. robustum [11]. However, despite the fact that the stereochemical basis
was established, considerable confusion concerning the absolute configuration
remained in the current literature [8][11]3) [14]. The reasons for these inconsistencies
are not obvious. It can be assumed that they might have a rather trivial origin, most
probably due to the different nomenclatures and numbering systems1) as well as to
unconventional, ambiguous drawings of the molecule in different orientations, C2-
rotations leading to the enantiomer (e.g., [8]), or reading and printing errors4).
Mainly due to methodological reasons5), (ꢀ)-centrolobine ((ꢀ)-1) was recently
discovered as an ideal synthetic target to exploit [15 – 30], the hallmark being the report
on its first enantioselective total synthesis [17]. It was achieved by reductive cyclization
of an optically active hydroxysulfinyl ketone and for the first time ever confirmed the
(2S,6R)-configuration of (ꢀ)-1 as earlier proposed by us [4]. In the course of further
synthetic activities, the stereoselective construction of the tetrahydro-2H-pyran ring has
been achieved by Prins-type cyclization [18] and secondary modifications thereof [19],
by reductive etherification of d-(trialkylsilyloxy)-substituted ketones [20], by cross-
metathesis procedures [21] and related strategies [22][23], by a diastereoselective ring
rearrangement metathesis – isomerization sequence [15], by Maitland – Japp reaction
[24], by intramolecular oxy-Michael reaction [25], by Lewis-acid mediated reactions
such as cyclization of a 1,5-diol [26] or opening of an epoxide precursor [23], by hetero-
Diels – Alder reaction between 4-aryl-2-(silyloxy)buta-1,3-dienes and phenylpropargyl-
aldehyde (¼ 3-phenylprop-2-ynal) derivatives [27] or related enantioselective multi-
step procedures [28]6), by intramolecular Barbier-type cyclization of iodoesters with an
organolithium base [29], and by stereoselective synthesis of cyclic ethers via Pd-
catalyzed intramolecular addition of alcohols to phosphonoallyl carbonates [30].
Several years ago, a single trans-configured congener of centrolobine was isolated
as a trace constituent of Alpinia blepharocalyx, i.e., (ꢀ)-(2R,6S)-3,4-didehydro-O-
demethylcentrolobine (¼(ꢀ)-(3S,7R)-5,6-didehydro-O-demethylcentrolobine3); (ꢀ)-
2) [31]. The absolute configuration of (ꢀ)-2 was assumed by biogenetic considerations
in connection with an earlier, erroneously assigned compound7). But this assignment is
2
)
)
)
It was reliably confirmed that C. robustum was confused with C. tomentosum and had to be
interchanged [11].
Although clarifying the absolute configuration was intended in [11], the stereodescriptors in the
enantiomeric centrolobols and centrolobines specified have to be interchanged.
The report on the synthesis of (ꢀ)-centrolobine ((ꢀ)-1) is such an example as [a]D ¼ þ60 (ee
> 98%) is specified for the target molecule [15].
3
4
5
6
7
)
)
)
For a review on strategies for the formation of tetrahydro-2H-pyrans in natural products, see [16].
The formula for (ꢀ)-centrolobine in the graphical abstract in [28] represents the (þ)-enantiomer.
This (ꢀ)-trans-compound had been reported to be a constituent of Alpinia blepharocalyx already
earlier [32]. However, our chemical argumentation clearly showed it to be erroneous [4]. Later, the
structure was revised to its (ꢀ)-cis-isomer ((2S,6S) or (3S,7S)3)) in an Erratum [33] without any
comment.

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not free from doubt as reliable syntheses and chiroptical comparisons [34 – 36] strongly
suggest that the natural compound is rather the enantiomer ((ꢀ)-(2S,6R) or (ꢀ)-
3R,7S)3))8) (Fig. 3).
Fig. 3. Structures of the naturally occurring (ꢀ)-3,4-didehydro-O-demethylcentrolobine [28] (left) and
proposed revision (right)
Very recently, the syntheses of trans-isomers of centrolobine have been reported,
too. Thus, (ꢀ)-(2S,6S)-(or (ꢀ)-(3S,7S)3))-epicentrolobine was prepared by a stereo-
selective C-glycosidation procedure as the key step [34], and all the four stereoisomers
were synthesized by a tandem ring-closing metathesis – isomerization reaction to a
monosubstituted dihydropyran and introduction of the 4-methoxyphenyl group by a
diazonium-mediated Heck reaction [35]. The synthetic pathways unambiguously
establish the absolute configurations and the coherence with the chiroptical data7).
1.3. The Biomimetic Concept. In spite of all the synthetic efforts, one subtle fact
remained undiscussed from the first account [6][7] until to the very recent ones
[8][15][17 – 30]: the unambiguous location of the MeO group. It was never assigned by
spectrosopic data but inferred by the synthesis of (ꢁ)-centrolobine and its O-methyl
derivative and comparison with the natural product [6][7]. Although the respective
isomer (ꢃisocentrolobineꢄ, Fig. 1) was not known, it was anticipated obviously by
implication that the latter would significantly differ from its parent9). As a matter of
fact, the potential occurrence of the regioisomer was never taken into consideration,
and the position of the MeO group in the centrolobines was neither questioned ever
since.
This fundamental aspect, the persistent structural inconsistencies, and the fact that
of the 8 isomeric 2,6-(OH/MeO)-disubstituted tetrahyro-2H-pyrans only (ꢀ)-1 is being
exploited, prompted us to re-investigate the centrolobine chemistry [36 – 38]. Utilizing
our experience with the tetrahydro-2H-pyrans B from Plectranthus species (Scheme 1)
[3][4], the target molecules were prepared directly from their linear diarylheptanoid
precursors by oxidative cyclization as the key step. The pathway is straightforward as it
retains the configuration at C(3) of the precursors which becomes C(6) in the
heterocycles. Moreover, it would lead to the sterically most favorable diequatorial
8
)
It has been shown conclusively that epimerization of (þ)-trans-centrolobine yields the respective
(ꢀ)-cis-2(73))-epimer and vice versa [35]. Hence, from the comparison of a series of structurally
unambiguously established compounds, it can be concluded that the benzyloxy chromophore
determines the sign of the optical rotation in terms of (2R) (or (7R)3)) > 0 and vice versa. According
to chemical transformations [32][36], the additional C¼C bond does not seem to affect the
chiroptical data significantly.
9
)
This is an example of circular reasoning. The following article [37] demonstrates that the spectral
data of the regioisomers are highly similar.

Helvetica Chimica Acta – Vol. 93 (2010)
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arrangement of the substituents in the transition state, hence affording the 2,6-cis-
tetrahydro-2H-pyrans as the main products (Scheme 2).
Scheme 2
This approach is different from the previous ones [15 – 30][34][35] and constitutes
a real biomimetic synthesis of the centrolobine congeners. Moreover, the concept
enables the access to the hitherto unknown ꢃisocentrolobineꢄ series by appropriate
selection of R1 and R2 (Scheme 2).
2. Synthesis and Characterization of the (þ)- and (ꢀ)-Centrolobines. – 2.1. (þ)-(S)-
and (ꢀ)-(R)-O-Methylcentrolobol ((þ)- and (ꢀ)-11, resp.). The precursors (þ)- and
(ꢀ)-11 were obtained from the homoallylic alcohols (þ)- and (ꢀ)-7 followed by cross-
metathesis with 4-allylanisole (6) and catalytic hydrogenation of the resulting
diarylheptanoids (þ)- and (ꢀ)-10 (Scheme 3): Enantioselective allylation of the
aldehyde 5 (obtained from 3 via 4) under Keck conditions [39] yielded (þ)-(R)-7 and
(ꢀ)-(S)-7 (ee > 98%, ee > 99%, resp.). The absolute configurations were verified by
means of the respective O-MTPA derivatives [40] 8 and 9 and proved to be as expected
[39] (MPTA ¼ methoxy(phenyl)(trifluoromethyl)acetyl)10). Treating (þ)- and (ꢀ)-7
with 6 in the presence of Hoveyda – Grubbs (2nd gen.) catalyst HG-II [41] at ꢀ 78811)
furnished the diarylheptanoid homoallylic alcohols (þ)- and (ꢀ)-10 ((E)/(Z) mixture
ca. 8 :1), and hydrogenation afforded the (þ)-(S)- and (ꢀ)-(R)-O-Methylcentrolobols
(þ)- and (ꢀ)-11 (ee > 97% and > 98%, resp.).
10
)
)
This additional verification was performed to exclude further potential errors.
11
Unexpectedly, the metathesis reaction succeeded only at ꢀ788. Applying the common protocols
(ꢂroom temp.) resulted in complete decomposition. Moreover, the yields were strongly dependent
on the quality of the used glassware, and reproducibility was only obtained when soaking the
reaction vessels in 10% HCl solution during 16 h before use [36] (see Exper. Part).

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Scheme 3
a) BnBr, K2CO3, DMF, 808. b) DIBAH (diisopropylaluminium hydride), CH2Cl2, ꢀ 788. c) (ꢀ)-(S)-
[1,1’-Binaphthalene]-2,2’-diol/(iPrO)4Ti, CH2Cl2, reflux. d) CH2¼CHCH2SnBu3, ꢀ 788 !ꢀ 208. e) (þ)-
(R)-[1,1’-Binaphthalene]-2,2’-diol/(iPrO)4Ti, CH2Cl2, reflux. f) (ꢀ)-(R)-MTPA-Cl, DMAP (N,N-
dimethylpyridin-4-amine), Et3N, r.t. g) 6, Hoveyda – Grubbs (2nd generation) catalyst HG-II, MeOH,
ꢀ 788 ! r.t. h) H2, 10% Pd/C, CH2Cl2, r.t. i) Ac2O, Et3N, CH2Cl2, ꢀ 58. j) DDQ (4,5-dichloro-3,6-
dioxocyclohexa-1,4-diene-1,2-dicarbonitrile), CH2Cl2, ꢀ 108. k) NaOH, MeOH, H2O, r.t. l) 4-
BrC6H4COCl, DMAP, Et3N, r.t.

Helvetica Chimica Acta – Vol. 93 (2010)
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2.2. Centrolobines (þ)- and (ꢀ)-1. The key step of the synthesis is the oxidative
cyclization of the O-methylcentrolobols (þ)- and (ꢀ)-11 with DDQ (Schemes 3 and 4).
This dehydrating agent is considered as a chemical equivalent of phenol oxidase
[3][4][42], was successful in earlier applications [3][4], and proved to be highly
superior to other oxidants (e.g., Ag2O, Ag2CO3, cerium(IV) ammonium nitrate
(CAN), K4[Fe(CN)6]) [36]. But when treating (þ)-11 with DDQ, mainly decom-
position occurred, and only traces of the expected centrolobine (þ)-1 could be
detected. Obviously, besides the desired intermediate (þ)-11ox, the quinone methide
(þ)-11ox’ was preferentially formed, thus yielding the instable oxetane 1512
)
(Scheme 4). The cyclization succeeded when the O-protected O-methylcentrolobols
(þ)- and (ꢀ)-12 were treated with DDQ to afford the O-acetylcentrolobines (þ)- and
(ꢀ)-13 in low yield (ca. 8%). However, the reaction proceeded mildly, and ca. 80% of
starting material was recovered that could be recycled. After saponification, the target
centrolobines (þ)- and (ꢀ)-1 were isolated (ee > 97% and > 98%, resp.). The
respective trans-isomers (þ)- and (ꢀ)-2 were not detected. Finally, the structure of the
synthetic (ꢀ)-(2S,6R)-1 was confirmed by an X-ray crystallographic analysis of its 4-
bromobenzoate 14 (Fig. 4)13).
Scheme 4
However, this outcome does not establish the consistency of the synthetic
centrolobines with the natural products. As discussed above (Sect. 1.3), the position
of the Me group in the latter is still not assured in the absence of the isomers. An X-ray
crystallographic analysis of an authentic sample of natural (ꢀ)-1 from Brosimum
12
)
Directed preparation of such oxetanes showed that they are formed but the structures could only be
assigned tentatively [38]. The instability of the compounds prevented closer investigations.
The full data set is summarized in the Table (see Exper. Part). CCDC-765627 and -765628 contain
the supplementary crystallographic data for (ꢀ)-1 and 14. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
13
)

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Fig. 4. Molecular structure of the synthetic 4-bromobenzoate 14 with refinement of the absolute structure
parameter. For reasons of clarity, the atom numbering is restricted to the tetrahydro-2H-pyran moiety;
50% probability ellipsoids.
potabile [8] furnished the conclusive evidence and established the position of the Me
)
group as proposed [6][7] (Fig. 5)14 15).
Fig. 5. Molecular structure of natural (ꢀ)-centrolobine ((ꢀ)-1) from Brosimum potabilis. For reasons of
clarity, the atom numbering is restricted to the tetrahydro-2H-pyran moiety; 50% probability ellipsoids.
3. Remarks. – Although the constitution of the natural centrolobines was correctly
assigned in the original reports [6][7], a fact that attests fine chemical intuition to the
authors, we consider our investigations beneficial. Besides the elucidation of a never
questioned subtle issue, they constitute the first straightforward biomimetic approach
from linear diarylheptanoids to 2,6-disubstituted 2H-tetrahydropyrans, and the general
synthetic protocol provides access to the hitherto unknown ꢃisoꢄ series [37][38].
Moreover, the correlation of the chiroptical data and the absolute configurations could
14
´
)
)
Obtained from Prof. Dr. Dorila Pilo-Veloso, Departamento de Quimica, Universidade Federal da
Minas Gerais, Belo Horizonte, Brazil.
This is the sole X-ray crystallographic analysis of a natural centrolobine congener.
15

Helvetica Chimica Acta – Vol. 93 (2010)
1289
be confirmed as postulated in an earlier review article [4]. Because the O-
methylcentrolobols ((þ)- and (ꢀ)-11) are not genuine plant constituents16), biogenetic
considerations suggest that the precursors of the (þ)- and (ꢀ)-centrolobines are the
(þ)- and (ꢀ)-centrolobols (Fig. 1). Phenol oxidation produces the sterically favored
2,6-disubstituted tetrahydro-2H-pyrans ((þ)- and (ꢀ)-O-demethylcentrolobines [9 –
11], Fig. 1) with retention of the configuration at C(3). Accidentally, the sign of the
optical rotation is retained, too. As a matter of fact, only one enantiomeric series was
isolated from a specific plant species [9 – 11]. The final biogenetic step is a
regioselective O-methylation affording (þ)-1 and (ꢀ)-1, respectively.
´
We are highly indebted to Prof. Dr. Dorila Pilo-Veloso, Departamento de Quimica, ICEX,
ˆ
Universidade Federal da Minas Gerais, Av. Antonio Carlos, 6627 Belo Horizonte-MG., CEP 31, 270-901
Brazil, for the generous gift of natural (ꢀ)-centrolobine. We thank PD Dr. A. Linden, head of the X-ray
department of our institute, for the high-quality X-ray crystallographic analyses. The financial support of
the project by the Swiss National Science Foundation is gratefully acknowledged.
Experimental Part
1. General. Air- and moisture-sensitive reagents and reactions were stored/performed in a Gloveboxꢅ
(B. Braun, Labmaster) under standard precautions. Enantioselective allylations were performed with
(þ)-(R)- and (ꢀ)-(S)-[1,1’-binaphthalene]-2,2’-diol ((þ)-(R)- and (ꢀ)-(S)-BINOL, resp.; puriss.,
Aldrich 246948 and 246956, resp.; ee > 99%), (iPrO)4Ti (purum, Fluka 87560), and allyl(tributyl)-
stannane (purum, Fluka 06070). The metathesis reactions were performed with Hoveyda – Grubbs 2nd
generation catalyst HG-II (99%, Aldrich 569755; ee > 99%) and 4-allylanisole (¼1-methoxy-4-(prop-2-
en-1-yl)benzene; 6; purum, Fluka 05820). Prior to use, the reaction vessels were soaked in 10% HCl soln.
(16 h) and dried at 2008 (24 h)11). The MTPA derivatives were prepared with (ꢀ)-(aR)- and (þ)-(aS)-a-
methoxy-a-(trifluoromethyl)benzeneacetyl chloride ((ꢀ)-(R)- and (ꢀ)-(S)-MTPA-Cl, resp.; Fluka
65363 and 65365, resp.; Chira Select, ee > 99.5%). TLC: Merck 60 F254 silica-gel (SiO2) plates; detection
by UV254 light, by spraying with ꢃmostainꢄ soln. ((NH4)6Mo7O24 · 4 H2O (40 g), Ce(SO4)2 (0.8 g), 10%
H2SO4 (800 ml)) and heating (blue spots). Standard column chromatography (CC): SiO2 60 (40 – 63 mm,
Merck 109385). Anal. HPLC and ee-determination: Chiralcelꢀ OD-H column (5 mm, 250 ꢃ 4.6 mm;
Daicel Chemical Industries, Ltd.); flow rate 1 ml/min, at r.t.; Pharmacia-LKB HPLC pump 2248; HP-
1040M diode-array detection system and data handling with HP Chemstation for LC, Rev. A.04.02
(Hewlett-Packard). GC/MS: HP-5980 series II (GC), HP-5971 MSD (mass-selective detector, EI;
70 eV), and column HP 1 (phenyl(1%)-methylsiloxane cross-linked; 25 m ꢃ 0.2 mm, 0.53 mm) (Hewlett-
Packard); injector 1808, detector 3308; temp. programs: 1008 (2 min), 100 – 2408 (rate 208/min), and 2408
(10 min) (ꢃlowꢄ), or 1008 (2 min), 100 – 2908 (rate 208/min), and 2908 (25 min) (ꢃhighꢄ). M.p.: Mettler FP
5/52; uncorrected. [a]2D5: Perkin-Elmer-241-MC polarimeter with thermostat B. Braun Thermomix 1441,
10 cm cell; ee based on the integration of the peak areas of the anal. HPLC separations (RS > 1.5). IR:
Perkin-Elmer-Spectrum-One FT-IR spectrometer; intensity of the bands: T< 15% (vs), T¼ 15 – 30% (s),
T¼ 30 – 70% (m), and T> 70% (w); ˜n in cmꢀ1
.
1H- and 13C-NMR: Bruker-ARX-300 (300.0 and
75.4 MHz, resp.), -AV2 – 400 (400.0 and 100.6 MHz, resp.), -DRX-500 (500.0 and 125.7 MHz, resp.),
-AMX-600 or -DRX-600 (600.0 and 150.9 MHz, resp.) spectrometers; d in ppm rel. to Me4Si as internal
standard, J in Hz; all assignments are based on extensive interpretations of 2D spectra (1H,1H-COSY,
1H,1H-NOESY, 13C{1H}-, DEPT90, DEPT135, 1H,13C-COSY (HSQC), and 1H,13C-long-range
16
)
The O-methylcentrolobols are known as cleavage products of natural cyclic diarylheptanoids. (ꢀ)-
11 originates from (ꢀ)-centrolobine ((ꢀ)-1) [9] and from the macrocyclic diarylheptanoid aceroside
I [43]. A racemic compound with the constitution of O-methylisocentrolobol (Fig. 1) was reported
to be a degradation product of acerogenin B [44]. However, the position of the Me group was not
discussed as it followed from the parent.

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(HMBC)); spin systems are interpreted according to 1st-order approximation, although in several
complex cases, significant AB character indicates higher-order spectra. MS: Finnigan MAT 75, electron
impact (EI; 70 eV) or chemical ionization (CI) with NH3. Nomenclature and atom numbering: For
convenience, in particular with respect to the discussions in the General Part and to enable direct
spectroscopic comparisons, arbitrary atom numberings are used (Fig. 6); systematic names are given in
the headings.
Fig. 6. Arbitrary atom numbering for the diarylheptanes and the tetrahydro-2H-pyrans
2. 3-[4-(Benzyloxy)phenyl]propanal (¼4-(Phenylmethoxy)benzenepropanal; 5)17). To a suspension
of K2CO3 (33.3 g, 241 mmol) in anh. DMF (50 ml), 4-hydroxybenzenepropanoic acid (2; 10.0 g,
60.2 mmol) was added at r.t. Then benzyl bromide (35 ml, 295 mmol) was added at 08, and the mixture
stirred at 808 (3 d). Workup and CC (SiO2; hexane ! hexane/AcOEt 25 :1) gave benzyl 3-[4-
(benzyloxy)phenyl]propanoate (¼ phenylmethyl 4-(phenylmethoxy)benzenepropanoate; 4; 20.3 g,
97%) as colorless solid. Reduction of 4 (8.9 g, 25.7 mmol) in anh. CH2Cl2 (90 ml) with diisobutylalu-
minium hydride (DIBAH; 37 ml, 0.7 – 1.3 mol in CH2Cl2) at ꢀ 808, workup, and CC (SiO2; hexane/
AcOEt 9 :1) yielded 5 (5.04 g, 81%) as a colorless oil that solidified in the refrigerator.
Data of 4: Colorless solid. M.p. 45 – 468. Rf (hexane/Et2O 1:2) 0.45. GC (ꢃhighꢄ): tR 17 min 55 s. IR
(KBr): 3432w, 3067w, 3033m, 2959m, 2930m, 2896m, 2859m, 1725vs, 1611m, 1581m, 1513vs, 1497m,
1452w, 1420m, 1384s, 1293s, 1253vs, 1176s, 1141s, 1108s, 1081m, 1042s, 1028s, 968m, 951m, 924m, 904m,
1
859m, 828s, 815m, 792w, 754s, 734s, 696s, 602w, 583w, 536m, 503m, 462w. H-NMR (300 MHz, CDCl3):
7.48 – 7.31 (m, 2 PhCH2); 7.13 (AA’ of AA’BB’, 3J ¼ 8.7, HꢀC(2’), HꢀC(6’)); 6.92 (BB’ of AA’BB’, 3J ¼
8.7, HꢀC(3’), HꢀC(5’)); 5.14 (s, COOCH2Ph); 5.07 (s, PhCH2); 2.95 (t, 3J ¼ 7.7, CH2(3)); 2.68 (t, 3J ¼ 7.7,
CH2(2)). 13C-NMR (75.4 MHz, CDCl3): 172.7 (C(1)); 157.3 (C(4’)); 137.1, 135.9 (Ph); 132.8 (C(1’)); 129.2
(C(2’), C(6’)); 128.55, 128.5, 128.1, 127.9, 127.4 (Ph); 114.9 (C(3’), C(5’)); 70.0, 66.2 (PhCH2); 36.1 (C(2));
30.1 (C(3)). EI-MS: 346 (2, Mþ), 255 (4, [M ꢀ PhCH2]þ), 165 (1), 120 (1), 107 (1, C7H7Oþ), 91 (100,
PhCHþ2 ), 89 (2), 79 (1), 77 (2), 65 (10), 63 (1), 51 (2).
Data of 5: M.p. 45 – 478. Rf (hexane/Et2O 1:2) 0.29. GC (ꢃlowꢄ): tR 12 min 31 s. IR (KBr): 3415w,
3092w, 3064w, 3033m, 2930m, 2897m, 2861m, 2833m, 2732m, 1718vs, 1610m, 1580m, 1513vs, 1452s, 1407m,
1383s, 1313m, 1298m, 1239vs, 1176s, 1112m, 1079w, 1040m, 1028s, 1006s, 934w, 913m, 904m, 861m, 833m,
814s, 790m, 736s, 697s, 637w, 599w, 542m, 510w, 501w, 463w. 1H-NMR (300 MHz, CDCl3): 9.82 (t, 3J ¼ 1.5,
HꢀC(1)); 7.46 – 7.31 (m, PhCH2); 7.13 (AA’ of AA’BB’, 3J ¼ 8.7, HꢀC(2’), HꢀC(6’)); 6.93 (BB’ of
AA’BB’, 3J ¼ 8.7, HꢀC(3’), HꢀC(5’)); 5.06 (s, PhCH2); 2.92 (t, 3J(2,3) ¼ 7.5, CH2(3)); 2.75 (tt, 3J(2,3) ¼
3
7.5, J(1,2) ¼ 1.5, CH2(2)). 13C-NMR (75.4 MHz, CDCl3): 201.7 (C(1)); 157.3 (C(4’)); 137.1 (Ph); 132.6
(C(1’)); 128.5, 127.9, 127.4 (Ph); 129.2 (C(2’), C(6’)); 115.0 (C(3’), C(5’)); 70.0 (PhCH2); 45.4 (C(2)); 27.3
(C(3)). EI-MS: 240 (13, Mþ), 121 (1, C8H9Oþ), 107 (1, C7H7Oþ), 103 (1), 91 (100, PhCHþ2 ), 89 (4), 78
(3), 77 (7), 65 (22), 63 (5), 55 (2), 51 (6).
3. (þ)-(3R)- and (ꢀ)-(3S)-1-[4-(Benzyloxy)phenyl]hex-5-en-3-ol (¼(þ)-(aR)- and (ꢀ)-(aS)-4-
(Phenylmethoxy)-a-(prop-2-en-1-yl)benzenepropanol, resp.; (þ)- and (ꢀ)-7, resp.)18). To a suspension of
(ꢀ)-(S)-[1,1’-binaphthalene]-2,2’-diol (358 mg, 1.25 mmol) in anh. CH2Cl2 (10 ml) and powdered
activated molecular sieves 4 ꢆ (1.5 g), (iPrO)4Ti (379 ml, 1.25 mmol) was slowly added (N2, r.t.) and
the mixture refluxed (2 h). After evaporation in a stream of N2, the residue was taken up in anh. CH2Cl2
(10 ml), and 5 (3.00 g, 12.5 mmol) was added at r.t. After cooling to ꢀ 788, CH2¼CHCH2SnBu3 (4.8 ml,
17
)
)
The compound has been prepared earlier, but only selected physical data are reported [45].
The compounds have been prepared earlier, but only selected physical data are reported: (þ)-7 [46],
and (ꢀ)-7, e.g. [21][22].
18

Helvetica Chimica Acta – Vol. 93 (2010)
1291
15.5 mmol) was added, and the mixture kept at ꢀ 258 (90 h). Workup and CC (SiO2; hexane/Et2O 2 :1)
gave (þ)-7 (2.69 g, 76%; ee > 98%) as a colorless solid. Analogously, starting from (þ)-(R)-[1,1’-
binaphthalene]-2,2’-diol (394 mg, 1.37 mmol) in anh. CH2Cl2 (10 ml), molecular sieves 4 ꢆ (2.0 g),
(iPrO)4Ti (406 ml, 1.37 mmol), 5 (3.3 g, 13.7 mmol), and CH2¼CHCH2SnBu3 (4.9 ml, 15.8 mmol), we
obtained (ꢀ)-7 (2.79 g, 72%; ee > 99%) as a white solid. HPLC (Chiralcelꢀ OD-H, hexane/iPrOH 50 :1):
k’((þ)-7) ¼ 5.6, k’((ꢀ)-7) ¼ 4.5, RS ¼ 3.1).
Data of (þ)-7: M.p. 70 – 718. Rf (hexane/Et2O 1:1) 0.26. GC (ꢃlowꢄ): tR 17 min 11 s. [a]D ¼ þ13.6 (c ¼
0.62, EtOH). IR (KBr): 3509s, 3433s, 3061m, 3008m, 2940m, 2904m, 2855m, 1642m, 1614s, 1596m, 1583m,
1513vs, 1452s, 1437m, 1383s, 1345m, 1316m, 1294m, 1271m, 1253vs, 1220s, 1177s, 1148s, 1126s, 1078s,
1058m, 1043s, 1029m, 1000m, 951w, 911m, 862m, 850m, 825s, 816s, 784m, 762m, 749m, 734s, 695m, 665m,
585w, 565m, 552w, 516m, 491w, 463w. 1H-NMR (400 MHz, CDCl3): 7.46 – 7.32 (m, tt-like, 3J ꢄ 7.5, Ph); 7.14
(AA’ of AA’BB’, 3J ¼ 8.4, HꢀC(2’), HꢀC(6’)); 6.93 (BB’ of AA’BB’, 3J ¼ 8.4, HꢀC(3’), HꢀC(5’)); 5.84
3
3
2
4
(ddt, J ¼ 17.5, 9.8, 7.5, HꢀC(5)); 5.12 (dq-like, J ¼ 17.5, 9.8, J ꢄ J ꢄ 1, CH2(6)); 5.06 (s, PhCH2); 3.68
3
2
3
2
(br. quint., J ¼ 7.5, HꢀC(3)); 2.72 (dquint.-like, J ¼ 14.5, J ꢄ 8, CH2(1)); 2.27 (dquint.-like, J ¼ 14.5,
3J ¼ 7.5, CH2(4)); 1.77 (m, q-like, J ꢄ 8, CH2(2)); 1.67 (s, HOꢀC(3)). 13C-NMR (100.6 MHz, CDCl3):
3
157.0 (C(4’)); 137.2 (Ph); 134.6 (C(5)); 134.4 (C(1’)); 129.3 (C(2’), C(6’)); 128.5, 127.8, 127.4 (Ph), 118.2
(C(6)); 114.8 (C(3’), C(5’)); 70.0 (PhCH2); 69.9 (C(3)); 42.0 (C(2)); 38.6 (C(4)); 31.1 (C(1)). EI-MS: 282
(3, Mþ), 197 (5), 119 (1), 107 (3, C7H7Oþ), 91 (100, PhCHþ2 ), 89 (2), 78 (3), 77 (2), 65 (9), 63 (1), 55 (1),
51 (2).
Data of (ꢀ)-7: [a]D ¼ ꢀ14.4 (c ¼ 0.60, EtOH). All other data: identical with those of (þ)-7.
4. (S)-MTPA Derivatives 8 and 9 for the Confirmation of the Absolute Configuration. Each
homoallyl alcohol (þ)- or (ꢀ)-7 (each 12 mg, 0.043 mmol) was dissolved in anh. CH2Cl2 (1 ml) and Et3N
(24 ml, 0.172 mmol). DMAP (1 mg) and (þ)-(R)-MTPA-Cl (16 ml, 0.086 mmol) were added, and the
mixture was stirred at r.t. (4 h). Workup and CC (SiO2; hexane/CH2Cl2 1:2 ! hexane/CH2Cl2/AcOEt
2 :7:1) afforded the (S)-MTPA ester 8 (18 mg, 85%) or 9 (18.7 mg, 88%), resp., both as colorless, viscous
oils.
(3R)-1-[4-(Benzyloxy)phenyl]hex-5-en-3-yl (2S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate
( ¼ (aS)-a-Methoxy-a-(trifluoromethyl)benzeneacetic Acid (1R)-1-{2-[4-(Phenylmethoxy)phenyl]ethyl}-
but-3-en-1-yl Ester; 8): Rf (hexane/Et2O 1:1) 0.58. GC (ꢃhighꢄ): tR 23 min 30 s. 1H-NMR (400 MHz,
3
CDCl3): 7.60 – 7.55 (m, Ph); 7.46 – 7.30 (m, PhCH2); 7.01 (AA’ of AA’BB’, J ¼ 8.7, HꢀC(2’), HꢀC(6’));
3
3
6.91 (BB’ of AA’BB’, J ¼ 8.7, HꢀC(3’), HꢀC(5’)); 5.66 (ddt, J ¼ 17, 10, 6, HꢀC(5)); 5.19 (br. quint.,
3J ꢄ 6, HꢀC(3)); 5.05 (s, PhCH2); 5.04 (br. dq-like, 3J ¼ 17, 10, 2J ꢄ J ꢄ 1, CH2(6)); 3.57 (q, 5J(H,F) ¼ 1.1,
4
MeO); 2.59 (m, dquint.-like, w1/2 ꢄ 30, CH2(1)); 2.40 (tt, 3J ¼ 6, 4J ꢄ 1, CH2(4)); 1.94 (m, dquint.-like,
w1/2 ꢄ 30, CH2(2)). 13C-NMR (100.6 MHz, CDCl3): 166.2 (CO); 157.3 (C(4’)); 137.2 (PhCH2); 133.3
(C(1’)); 132.5 (C(5)); 132.3, 129.6 (Ph of MTPA); 129.2 (C(2’), C(6’)); 128.6 (PhCH2); 128.4 (Ph of
MTPA); 127.9 (PhCH2); 127.5, 127.4 (PhCH2, Ph of MTPA); 123.4 (q, 1J(C,F) ¼ 288, CF3); 118.5 (C(6));
114.9 (C(3’) C(5’)); 84.5 (q, 2J(C,F) ¼ 27.6, PhC(MeO)(CF3)CO); 76.0 (C(3)): 70.1 (PhCH2); 55.4
(MeO); 38.0 (C(4)); 35.3 (C(2)); 30.6 (C(1)). EI-MS: 498 (1, Mþ), 264 (1, [M ꢀ MTPA ꢀ H2O]þ), 223
(1), 197 (5), 189 (5), 184 (1), 184 (1), 145 (1), 139 (1), 131 (1), 127 (1), 119 (3), 115 (2), 107 (2, C7H7Oþ),
105 (4), 91 (100, PhCH2þ ), 77 (6), 65 (10), 51 (3).
(3S)-1-[4-(Benzyloxy)phenyl]hex-5-en-3-yl (2S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate
(¼(aS)-a-Methoxy-a-(trifluoromethyl)benzeneacetic acid (1S)-1-{2-[4-(Phenylmethoxy)phenyl]ethyl}-
but-3-en-1-yl Ester; 9): Rf (hexane/Et2O 1:1) 0.58. GC (ꢃhighꢄ): tR 23 min 19 s. 1H-NMR (400 MHz,
CDCl3): 7.61 – 7.58 (m, Ph); 7.45 – 7.29 (m, PhCH2); 6.98 (AA’ of AA’BB’, 3J ¼ 8.7, HꢀC(2’), HꢀC(6’));
6.88 (BB’ of AA’BB’, 3J ¼ 8.7, HꢀC(3’), HꢀC(5’)); 5.76 (ddt, 3J ¼ 17, 10, 7, HꢀC(5)); 5.19 (br. quint. 3J ꢄ
4
4
7, H ꢀC(3)); 5.12 (dq, 3J ¼ 17, 2J ꢄ J ꢄ 1, Htrans ꢀ C(6)); 5.11 (dq, 3J ¼ 10, 2J ꢄ J ꢄ 1, Hcis ꢀ C(6)); 5.04 (s,
PhCH2); 3.59 (q, 5J(H,F) ¼ 1.2, MeO); 2.45 (br. quint.-like, w1/2 ꢄ 20, CH2(1), CH2(4)); 1.88 (br. tq-like,
w1/2 ꢄ 15, CH2(2)). 13C-NMR (100.6 MHz, CDCl3): 166.2 (CO); 157.2 (C(4’)); 137.2 (PhCH2); 133.4
(C(1’)); 132.9 (C(5)); 132.3 (Ph of MTPA); 129.6 (Ph of MTPA); 129.2 (C(2’), C(6’)); 128.6 (PhCH2);
128.4 (Ph of MTPA); 127.9 (PhCH2); 127.4, 127.4 (PhCH2, Ph of MTPA); 123.4 (q, 1J ¼ 289, CF3); 118.6
2
(C(6)); 114.9 (C(3’), C(5’)); 84.5 (q, J(C,F) ¼ 27.6, PhC(MeO)(CF3)CO); 75.9 (C(3)); 70.1 (PhCH2);
55.5 (MeO); 38.3 (C(4)); 35.3 (C(2)); 30.3 (C(1)). EI-MS: 498 (1, Mþ), 264 (1, [M ꢀ MTPA ꢀ H2O]þ),

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Helvetica Chimica Acta – Vol. 93 (2010)
197 (4), 189 (3), 184 (1), 152 (1), 133 (1), 127 (1), 119 (1), 107 (1, C7H7Oþ), 105 (4), 91 (100, PhCH2þ ), 77
(4), 65 (9), 51 (4).
Dd(1H) ¼ d(S) ꢀ d(R) ¼ d(9) ꢀ d(8) (in Hz): CH2(1) ꢀ 56, CH2(2) ꢀ 24, HꢀC(3) 0, CH2(4) þ 20,
HꢀC(5) þ 40, and CH2(6) þ 30. The relative displacements [40] confirm the expected [39] absolute
configuration at C(3).
5. (þ)- and (ꢀ)-(5E)-4’-O-(Benzyloxy)-5,6-didehydro-4’’-O-methylcentrolobol (¼(þ)-(3R,5E)- and
(ꢀ)-(3S,5E)-1-[4-(Benzyloxy)phenyl]-7-(4-methoxyphenyl)hept-5-en-3-ol ¼ (þ)-(aR)- and (ꢀ)-(aS)-a-
[(2E)-4-(4-Methoxyphenyl)-but-2-en-1-yl]-4-(phenylmethoxy)benzenepropanol, resp.; (þ)- and (ꢀ)-10,
resp.). To a soln. of HG-II (22 mg, 0.052 mmol) in anh. MeOH (2 ml) at ꢀ 788, a soln. of (þ)-7 (104 mg,
0.368 mmol) and 4-allylanisole (215 mg, 1.46 mmol; 6) in anh. MeOH (2 ml) was added under Ar. The
mixture was stirred (1 h) at ꢀ 788 and then allowed to warm to r.t. for 6 h, when another portion of 6
(105 mg, 0.716 mmol) was added and stirred for 1 h at r.t. After evaporation to dryness in a stream of N2,
CC (SiO2; hexane/CH2Cl2/AcOEt 5 :14 :1) afforded starting (þ)-7 (28 mg, 27%) that could be recycled,
and (þ)-10 (48 mg, 32%; (E)/(Z) ca. 8 :119) as colorless plates. Analogously, starting from (ꢀ)-7 (50 mg,
0.177 mmol), 5 (106 mg, 0.715 mmol) in anh. MeOH (3 ml), HG-II (11 mg, 0.017 mmol), and further
addition of 5 (51 mg, 0.344 mmol), we obtained (ꢀ)-7 (24 mg, 34%) and (ꢀ)-10 (12 mg, 24%; (E)/(Z) ca.
8 :1)19).
Data of (þ)-10: M.p. 78 – 838. Rf (hexane/Et2O 1:2) 0.32. [a]D ¼ þ2.3 (c ¼ 0.65, EtOH). IR (KBr):
3366m, 3061w, 3032w, 2996w, 2931m, 2857m, 2838m, 1606m, 1582m, 1511vs, 1453m, 1383m, 1295m,
1246vs, 1176s, 1100m, 1063m, 1035s, 968m, 910w, 887m, 831m, 807m, 780w, 739m, 697m, 641w, 608w, 543w,
1
3
522w. H-NMR (300 MHz, CDCl3)20): 7.45 – 7.30 (m, Ph); 7.14 – 7.06 (2 AA’ of AA’BB’, t-like, J ¼ 8.6,
HꢀC(2’), HꢀC(2’’), HꢀC(6’), HꢀC(6’’)); 6.90 (BB’ of AA’BB’, 3J ¼ 8.6, HꢀC(3’), HꢀC(5’)); 6.83 (BB
of AA’BB’, 3J ¼ 8.6, HꢀC(3’’), HꢀC(5’’)); 5.69 (X of ABMX, dt, 3J(6,5) ¼ 15.1, 3J(6,7) ¼ 6.7, HꢀC(6));
5.29 (br. dt, 3J(5,6) ¼ 15.1, 3J(5,4) ¼ 7.8, 4J(5,3) ꢄ 1, HꢀC(5)); 5.04 (s, PhCH2); 3.79 (s, MeOꢀC(4’’)); 3.64
(M of ABMX, quint.-like, 3J ꢄ 7, H ꢀC(3)); 3.31 (d, 3J(7,6) ¼ 6.7, CH2(7)); 2.72, 2.64 (AB of ABXY, 2J ¼
14.3, 3J ¼ 7.7, 6.4, CH2(1)); 2.26 (A of ABMX, 2J ¼ 13.7, 3J ꢄ 5, 4J < 1, HAꢀC(4)); 2.17 (B of ABMX, 2J ¼
13.7, 3J ¼ 7.2, HBꢀC(4)); 1.77 (XY of ABXY, q-like, CH2(2)); 1.57 (s, HOꢀC(3)). 13C-NMR (100.6 MHz,
CDCl3)20): 157.9 (C(4’)); 157.0 (C(4’’)); 137.2 (Ph), 134.4 (C(1’)); 133.6 (C(1’’), C(6)); 129.3 (C(2’), C(2’’),
C(6’), C(6’’)); 128.5, 127.9, 127.5 (Ph); 126.9 (C(5)); 114.7 (C(3’’), C(5’’)); 113.9 (C(3’), C(5’)); 70.2
(C(3)); 70.0 (PhCH2); 55.3 (MeOꢀC(4’’)); 40.7 (C(4)); 38.6 (C(2)); 38.2 (C(7)); 31.1 (C(1)). EI-MS: 402
(10, Mþ), 211 (8), 197 (9), 147 (17), 121 (16, C8H9Oþ), 107 (8, C7H7Oþ), 91 (100, PhCHþ2 ), 77 (3), 65 (5).
Data of (ꢀ)-10: [a]D ¼ ꢀ2.8 (c ¼ 0.64, EtOH). All other data: identical with those of (þ)-10.
6. (þ)- and (ꢀ)-4’’-O-Methylcentrolobol (¼(þ)-4-[(3S)- and (ꢀ)-4-[(3R)-3-Hydroxy-7-(4-
methoxyphenyl)heptyl]phenol ¼ (þ)-(aS)- and (ꢀ)-(aR)-a-[2-(4-Hydroxyphenyl)ethyl]-4-methoxyben-
zenepentanol, resp.; (þ)- and (ꢀ)-11, resp.). The soln. of (þ)-10 (200 mg, 0.497 mmol) in anh. CH2Cl2
(10 ml) was hydrogenated over 10% Pd/C (37 mg, 0.035 mmol) by stirring under a slight H2 pressure
(rubber balloon) at r.t. (2 d). Usual workup and CC (SiO2; hexane/CH2Cl2/AcOEt 5 :14 :1) afforded
(þ)-11 (128 mg, 82%; ee > 97%) as a colorless, viscous oil that solidified in the refrigerator. Analogously,
starting from (ꢀ)-10 (260 mg, 0.646 mmol) and 10% Pd/C (48 mg, 0.048 mmol), we obtained (ꢀ)-11
(174 mg, 86%; ee > 98%). HPLC (Chiralcelꢀ OD-H, hexane/iPrOH 8 :1): k’((þ)-11) ¼ 10.7, k’((ꢀ)-11) ¼
8.2, RS ¼ 2.7.
Starting from (þ)- and (ꢀ)-7, resp., compounds (þ)- and (ꢀ)-11, resp., could also be prepared by a
one-pot procedure: When the metathesis was performed in CH2Cl2, the crude product mixture was
hydrogenated in situ and purified by CC as described above. A typical protocol with (þ)-7 (200 mg,
0.708 mmol) and 4-allylanisole (6, 429 mg, 2.896 mmol) in anh. CH2Cl2 yielded after hydrogenation and
CC, (þ)-11 (93 mg, 42%; ee > 97%). Analogously, (ꢀ)-11 was isolated (102 mg, 46%; ee > 98%)21). This
protocol failed when the metathesis was performed in MeOH.
1
19
20
21
)
)
)
Estimated according to the intensities of the H-NMR signals of CH2(7).
Only the (E)-isomer is specified.
The hydrogenolysis product of natural (ꢀ)-1 was reported to be (ꢀ)-11 (m.p. 73 – 758; [a]D ¼ ꢀ8.6)
[9]. To the cleavage product of the macrocyclic diarylheptanoid aceroside I, structure (ꢀ)-11 was
assigned, too (m.p. 80.5 – 81.58; [a]D ¼ ꢀ7.5) [43].

Helvetica Chimica Acta – Vol. 93 (2010)
1293
Data of (þ)-11: M.p. 74 – 768. Rf (hexane/Et2O 1:4) 0.45. GC (ꢃhighꢄ): tR 18 min 2 s. [a]D ¼ þ9.5 (c ¼
0.4, EtOH). IR (KBr): 3425vs, 3326s, 3250m, 3070w, 3027w, 3010w, 2933s, 2914s, 2853s, 1610m, 1592m,
1512vs, 1462m, 1453m, 1436m, 1345m, 1320w, 1300m, 1265s, 1234vs, 1207m, 1198m, 1179s, 1161m, 1135m,
1104m, 1095m, 1073w, 1059m, 1031m, 996w, 983w, 924w, 909w, 868w, 843m, 830m, 819m, 808m, 788w,
1
771w, 751w, 728w, 713w, 638w, 583m, 541m, 518m. H-NMR (400 MHz, CDCl3): 7.08 (AA’ of AA’BB’,
3J ¼ 8.7, HꢀC(2’’), HꢀC(6’’)); 7.03 (AA’ of AA’BB’, 3J ¼ 8.6, HꢀC(2’), HꢀC(6’)); 6.83 (BB’ of AA’BB’,
3J ¼ 8.7, HꢀC(3’’), HꢀC(5’’)); 6.74 (BB’ of AA’BB’, 3J ¼ 8.6, HꢀC(3’), HꢀC(5’)); 5.92 (br. s,
HOꢀC(4’)); 3.79 (s, MeOꢀC(4’’)); 3.64 (m, br. quint.-like, 3J ꢄ 7, H ꢀC(3)); 2.70 (A of ABXY, 2J ¼ 14.0,
3J ¼ 9.3, HAꢀC(1)); 2.60 (B of ABXY, 2J ¼ 14.0, 3J ¼ 6.8, HBꢀC(1)); 2.55 (t, 3J ¼ 7.6, CH2(7)); 1.74 (XYof
ABXY, m, w1/2 ꢄ 30, CH2(2)); 1.61 (m, w1/2 ꢄ 20, CH2(6)); 1.55 – 1.43 (m, CH2(4), HꢀC(5), HOꢀC(3));
1.36 (m, br. t-like, w1/2 ꢄ 15, HꢀC(5)). 13C-NMR (100.6 MHz, CDCl3): 157.6 (C(4’’)); 153.9 (C(4’)); 134.7
(C(1’’)); 133.8 (C(1’)); 129.4 (C(2’), C(6’)); 129.2 (C(2’’), C(6’’)); 115.3 (C(3’), C(5’)); 113.7 (C(3’’),
C(5’’)); 71.5 (C(3)); 55.2 (MeOꢀC(4’’)); 39.1 (C(2)); 37.2 (C(4)); 34.9 (C(7)); 31.6 (C(6)); 31.1 (C(1));
25.1 (C(5)). EI-MS: 314 (4, Mþ), 296 (5, [M ꢀ H2O]þ), 281 (6), 207 (28), 193 (3), 188 (5), 177 (4), 174
(6), 158 (2), 147 (28), 134 (23), 131 (3), 121 (100, C8H9Oþ), 115 (3), 107 (71, C7H7Oþ), 105 (3), 103 (4),
94 (4), 91 (28, PhCHþ2 ), 89 (4), 78 (10), 77 (20), 73 (8), 65 (11), 55 (8), 51 (7).
Data of (ꢀ)-11: [a]D ¼ ꢀ9.8 (c ¼ 0.55, EtOH). All other data: identical with those of (þ)-11.
7. (þ)- and (ꢀ)-4’-(Acetyloxy)-4’’-methoxycentrolobol (¼(þ)-4-[(3S)- and (ꢀ)-4-[(3R)-3-Hydroxy-
7-(4-methoxyphenyl)heptyl]phenyl Acetate ¼ (þ)-(aS)- and (ꢀ)-(aR)-a-{2-[4-(Acetyloxy)phenyl]ethyl}-
4-methoxybenzenepentanol, resp.; (þ)- and (ꢀ)-12, resp.). A soln. of (þ)-11 (60 mg, 0.191 mmol) in anh.
CH2Cl2 (2 ml) was treated with Ac2O (20 ml, 0.212 mmol) and Et3N (135 ml, 0.97 mmol) at ꢀ 58 (2 h).
Workup and CC (SiO2; hexane ! hexane/CH2Cl2/AcOEt 2 :7:1) gave (þ)-12 (63 mg, 92%) as a white
solid. Analogously, starting from (ꢀ)-11 (100 mg, 0.318 mmol), Ac2O (31 ml, 0.328 mmol), and Et3N
(225 ml, 1.11 mmol), we obtained (ꢀ)-12 (109 mg, 96%).
Data of (þ)-12: M.p. 65 – 668. Rf (hexane/Et2O 1:4) 0.31. [a]D ¼ þ7.7 (c ¼ 0.5, CHCl3). IR (KBr):
3313m, 3229m, 3031w, 2931s, 2856m, 1760vs, 1612m, 1584w, 1513vs, 1463m, 1454m, 1443m, 1419w, 1369m,
1326w, 1301m, 1246vs, 1216vs, 1198vs, 1164s, 1137m, 1104m, 1073m, 1064m, 1035m, 1020m, 938w, 912m,
869m, 844m, 820m, 769w, 753w, 728w, 642m, 596w, 576m, 518m, 497w. 1H-NMR (400 MHz, CDCl3): 7.19
(AA’ of AA’BB’, 3J ¼ 8.5, HꢀC(2’), HꢀC(6’)); 7.09 (AA’ of AA’BB’, 3J ¼ 8.7, HꢀC(2’’), HꢀC(6’’)); 7.00
(BB’ of AA’BB’, 3J ¼ 8.5, HꢀC(3’), HꢀC(5’)); 6.83 (BB’ of AA’BB’, 3J ¼ 8.7, HꢀC(3’’), HꢀC(5’’)); 3.79
(s, MeOꢀC(4’’)); 3.61 (m, sept.-like, w1/2 ꢄ 15, HꢀC(3)); 2.78 (ddd, 2J ¼ 14, 3J ¼ 9.7, 5.8, HꢀC(1)); 2.65
(ddd, 2J ¼ 14, 3J ¼ 9.7, 6.8, HꢀC(1)); 2.57 (t, 3J ¼ 7.6, CH2(7)); 2.29 (s, MeCOOꢀC(4’)); 1.74 (m, tquint.-
like, w1/2 ꢄ 35, CH2(2)); 1.63 (m, w1/2 ꢄ 20, CH2(6)); 1.54 – 1.42 (m, CH2(4), HꢀC(5), HOꢀC(3)); 1.36
(m, br. t-like, w1/2 ꢄ 15, HꢀC(5)). 13C-NMR (100.6 MHz, CDCl3): 169.6 (CO); 157.6 (C(4’’)), 148.7
(C(4’)); 139.7 (C(1’)); 134.6 C(1’’)); 129.2 (C(2’), C(6’)); 129.2 (C(2’’), C(6’’)); 121.3 (C(3’), C(5’)); 113.7
(C(3’’), C(5’’)); 71.1 (C(3)); 55.2 (MeOꢀC(4’’)); 39.0 (C(2)); 37.4 (C(4)); 34.9 (C(7)); 31.6 (C(6)); 31.3
(C(1)); 25.1 (C(5)); 21.1 (MeCOOꢀC(4’)). EI-MS: 356 (22, Mþ), 338 (9, [M ꢀ H2O]þ), 314 (7), 296 (61,
[M ꢀ AcOH]þ), 189 (9), 188 (10), 147 (33), 134 (39), 121 (100, C8H9Oþ), 107 (64, C7H7Oþ), 91 (9,
PhCHþ2 ), 77 (8), 43 (8).
Data of (ꢀ)-12: [a]D ¼ ꢀ8.1 (c ¼ 0.6, CHCl3). All other data: identical with those of (þ)-12.
8. (þ)- and (ꢀ)-O-Acetylcentrolobine (¼(þ)-(2R,6S)- and (ꢀ)-(2S,6R)-6-{2-[4-(Acetyloxy)phenyl]-
ethyl}-2-(4-methoxyphenyl)tetrahydro-2H-pyran ¼ (þ)-4-{2-[(2S,6R)- and (ꢀ)-4-{2-[(2R,6S)-6-(4-Me-
thoxyphenyl)tetrahydro-2H-pyran-2-yl]ethyl}phenyl Acetate ¼ (þ)-4-{2-[(2S,6R)- and (ꢀ)-4-{2-
[(2R,6S)-Tetrahydro-6-(4-methoxyphenyl)-2H-pyran-2-yl]ethyl}phenol Acetate, resp.; (þ)- and (ꢀ)-13,
resp.). To a cooled (ꢀ108) soln. of (þ)-12 (54 mg, 0.151 mmol) in anh. CH2Cl2 (10 ml), DDQ (74 mg,
0.326 mmol) was added in a single portion and stirred (10 min). The crude mixture was quickly passed
through SiO2 (hexane/CH2Cl2/AcOEt 2 :7:1) and the filtrate evaporated. CC (SiO2; hexane/CH2Cl2/
AcOEt 5 :14 :1) afforded (þ)-13 (4 mg, 7%) as a colorless, viscous oil and starting (þ)-12 (41 mg, 76%)
that could be recycled. Analogously, starting from (ꢀ)-12 (80 mg, 0.224 mmol) and DDQ (98 mg,
0.432 mmol), we obtained (ꢀ)-13 (7 mg, 9%) and starting (ꢀ)-12 (64 mg, 80%).
Data of (þ)-13: Rf (hexane/Et2O 3 :2) 0.35. [a]D ¼ þ72.3 (c ¼ 0.62, CHCl3). IR (film): 3035m,
2999m, 2934vs, 2011s, 1763vs, 1613s, 1587m, 1514vs, 1456s, 1441s, 1369vs, 1329m, 1303s, 1247vs, 1194vs,
1079vs, 1037vs, 1019s, 944m, 911s, 834s, 812s, 767m, 638w, 589m, 573w, 549m. 1H-NMR (400 MHz,

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Helvetica Chimica Acta – Vol. 93 (2010)
3
CDCl3): 7.31 (AA’ of AA’BB’, J ¼ 8.6, HꢀC(2’), HꢀC(6’)); 7.19 (AA’ of AA’BB’,3J ¼ 8.5, HꢀC(2’’’),
HꢀC(6’’’)); 6.98 (BB’ of AA’BB’, 3J ¼ 8.5, HꢀC(3’’’), HꢀC(5’’’)); 6.89 (BB’ of AA’BB’, 3J ¼ 8.6,
HꢀC(3’), HꢀC(5’)); 4.30 (dd, 3J(2,3ax) ¼ 11.1, 3J(2,3eq) ¼ 2.0, HꢀC(2)); 3.81 (s, MeOꢀC(4’)); 3.46
(dddd, 3J(5ax,6) ¼ 10.7, 3J(5eq,6) ¼ 1.9, 3J(1’’, 6) ꢄ 8, 5, HꢀC(6)); 2.76 (m, ttt-like, 2J ꢄ 14, 3J ꢄ 7,
2
CH2(2’’)); 2.29 (s, MeCOOꢀC(4’’’)); 1.92 (m, w1/2 ꢄ 25, HꢀC(1’’), HeqꢀC(4)); 1.83 (br. dq-like, J ꢄ 11,
3J(2, 3eq) ꢄ J(3eq,4ax) ꢄ J(3eq,4eq) ꢄ 2, HeqꢀC(3)); 1.74 m, w1/2 ꢄ 25, HꢀC(1’’)); 1.63 (qt-like, 2J ꢄ
3
3
3
3
3J(3ax,4ax) ꢄ J(4ax,5ax) ꢄ 11, 3J(3ax,4eq) ꢄ J(4eq,5ax) ꢄ 3, HaxꢀC(4)); 1.62 (br. dq-like, 2J ꢄ 11,
3
3
3
3
3J(4ax,5eq) ꢄ J(4eq,5eq) ꢄ J(5eq,6) ꢄ 2, HeqꢀC(5)); 1.49 (m, qd-like, 2J ꢄ J(2,3ax) ꢄ J(3ax,4ax) ꢄ 10,
3J(3ax,4eq) ꢄ 4, HaxꢀC(3)); 1.33 (m, qd-like, 2J ꢄ J(4ax,5ax) ꢄ J(5ax,6) ꢄ 10, 3J(4eq,5ax) ꢄ 4,
HaxꢀC(5)). 13C-NMR (100.6 MHz, CDCl3): 169.7 (CO); 158.7 (C(4’)); 148.6 (C(4’’’)); 140.1 (C(1’’’));
135.9 (C(1’)); 129.4 (C(2’’’), C(6’’’)); 127.0 (C(2’), (6’)); 121.2 (C(3’’’), C(5’’’)); 113.6 (C(3’), C(5’)); 79.1
(C(2)); 77.0 (C(6)); 55.3 (MeOꢀC(4’)); 38.0 (C(1’’)); 33.4 (C(3)); 31.3 (C(5)); 31.1 (C(2’’)); 24.0 (C(4));
21.1 (MeCOOꢀC(4’’’)). EI-MS: 354 (74, Mþ), 312 (48, [M ꢀ C2H2O]þ), 294 (5, [M ꢀ AcOH]þ), 218 (9),
191 (9), 174 (30), 150 (9), 149 (15), 148 (26), 147 (38), 137 (27), 135 (29), 134 (26), 133 (19), 121 (53,
C8H9Oþ), 107 (100, C7H7Oþ), 91 (16, PhCHþ2 ), 77 (14), 65 (6), 43 (18).
3
3
Data of (ꢀ)-13: [a]D ¼ ꢀ73.4 (c ¼ 1.24, CHCl3). All other data: identical with those of (þ)-13.
9. (þ)- and (ꢀ)-Centrolobine (¼(þ)-(2R,6S)- and (ꢀ)-(2S,6R)-6-[2,4-(Hydroxyphenyl)ethyl]-2-(4-
methoxyphenyl)tetrahydro-2H-pyran ¼(þ)-4-{2-[(2S,6R)- and (ꢀ)-4-{2-[(2R,6S)-6-(4-Methoxyphenyl)-
tetrahydro-2H-pyran-2-yl]ethyl}phenol ¼ (þ)-4-{2-[(2S,6R)- and (ꢀ)-4-{2-[(2R,6S)-Tetrahydro-6-(4-me-
thoxyphenyl)-2H-pyran-2-yl]ethyl}phenol, resp.; (þ)- and (ꢀ)-1, resp.). To (þ)-13 (8 mg, 0.023 mmol) in
MeOH (2.5 ml), 10% aq. NaOH soln. (2.5 ml) was added and the mixture stirred at r.t. (4 h). Usual
workup, CC (SiO2; hexane/CH2Cl2/AcOEt 5 :14 :1), and recrystallization (hexane/AcOEt) gave (þ)-1
(6 mg, 85%; ee > 97%22) as colorless prisms. Analogously, starting from (ꢀ)-13 (14 mg, 0.039 mmol), we
obtained (ꢀ)-1 (11 mg, 89%; ee > 98%22). HPLC (hexane/iPrOH 20 :1): k’((þ)-1) ¼ 4.0, k’((ꢀ)-1) ¼ 3.7,
RS ¼ 0.95; HPLC (Chiralcelꢀ OD-H, hexane/iPrOH 50 :1): k’((þ)-1) ¼ 11.9, k’((ꢀ)-1) ¼ 10.9, RS ¼ 1.2
(not sufficient for a reliable ee-determination)22).
Data of (þ)-1: M.p. 93 – 948. Rf (hexane/Et2O 1:2) 0.20. [a]D ¼ þ89.3 (c ¼ 0.31, CHCl3). IR (KBr):
3389m, 3060w, 3025w, 2947m, 2925m, 2913m, 2859m, 2832m, 1611m, 1599m, 1588w, 1512vs, 1462m,
1452m, 1416w, 1370m, 1301m, 1244vs, 1208m, 1183m, 1172m, 1141w, 1112m, 1088s, 1069m, 1051m, 1036m,
1016w, 993w, 953w, 935w, 917w, 901w, 849w, 837m, 818m, 806m, 776w, 770w, 646w, 598w, 569m, 540m,
497w. 1H-NMR (400 MHz, CDCl3): 7.33 (AA’ of AA’BB’, 3J ¼ 8.6, HꢀC(2’), HꢀC(6’)); 7.04 (AA’ of
AA’BB’, 3J ¼ 8.5, HꢀC(2’’’), HꢀC(6’’’)); 6.90 (BB’ of AA’BB’, 3J ¼ 8.6, HꢀC(3’), HꢀC(5’)); 6.71 (BB’
of AA’BB’, 3J ¼ 8.5, HꢀC(3’’’), HꢀC(5’’’)); 5.14 (br. s, HOꢀC(4’’’)); 4.32 (dd, 3J(2,3ax) ¼ 11.0,
3J(2,3eq) ¼ 2.0, HꢀC(2)); 3.81 (s, MeOꢀC(4’)); 3.47 (dddd, 3J(5ax,6) ¼ 9.8, 3J(5eq,6) ¼ 1.8, 3J(1’’,6) ꢄ 7,
5, HꢀC(6)); 2.70 (m, ddt-like, 2J ¼ 14.0, 3J ꢄ 9, 6, CH2(2’’)); 1.92 (m, w1/2 ꢄ 25, HꢀC(1’’), HeqꢀC(4)); 1.84
2
3
3
3
(br. dq-like, J ꢄ 11, J(2,3eq) ꢄ J(3eq,4ax) ꢄ J(3eq,4eq) ꢄ 2, HeqꢀC(3)); 1.74 m, w1/2 ꢄ 25, HꢀC(1’’));
1.62 (m, w1/2 ꢄ 25, HaxꢀC(4), HeqꢀC(5)); 1.56 (qd-like, 2J ꢄ J(2,3ax) ꢄ J(3ax,4ax) ꢄ 10, 3J(3ax,4eq) ꢄ 3,
3
3
HaxꢀC(3)); 1.35 (qd-like, 2J ꢄ J(4ax,5ax) ꢄ J(5ax,6) ꢄ 10, 3J(4eq,5ax) ꢄ 4, HaxꢀC(5)). 13C-NMR
(100.6 MHz, CDCl3): 158.7 (C(4’)); 153.5 (C(4’’’)); 135.6 (C(1’)); 134.5 (C(1’’’)); 129.5 (C(2’’’), C(6’’’));
127.1 (C(2’), C(6’)); 115.1 (C(3’’’), C(5’’’)); 113.6 (C(3’), C(5’)); 79.2 (C(2)); 77.3 (C(6)); 55.3
(MeOꢀC(4’)); 38.2 (C(1’’)); 33.2 (C(3)); 31.2 (C(5)); 30.7 (C(2’’)); 24.0 (C(4)). EI-MS: 312 (72, Mþ),
294 (5, [M ꢀ H2O]þ), 191 (6), 187 (6), 174 (30), 160 (9), 149 (22), 148 (21), 147 (32), 137 (19), 135 (16),
134 (19), 133 (16), 121 (60, C8H9Oþ), 107 (100, C7H7Oþ), 91 (10, PhCHþ2 ), 77 (11).
3
3
Data of (ꢀ)-1: [a]D ¼ ꢀ91.0 (c ¼ 0.78, CHCl3). All other data: identical with those of (þ)-1.
10. (2R,6S)-6-{2-{4-[(4-Bromobenzoyl)oxy]phenyl}ethyl}-2-(4-methoxyphenyl)tetrahydro-2H-pyran
(¼4-{2-[(2R,6S)-6-(4-Methoxyphenyl)tetrahydro-2H-pyran-2-yl]ethyl}phenyl 4-Bromobenzoate ¼ 4-{2-
[(2R,6S)-Tetrahydro-6-(4-methoxyphenyl)-2H-pyran-2-yl]ethyl}phenol 4-Bromobenzoate; 14). To a
soln. of (ꢀ)-1 (8 mg, 0.026 mmol) and Et3N (1 ml, 0.051 mmol) in anh. CH2Cl2 (2 ml), 4-bromobenzoyl
22
)
Although the peaks are nearly base-line separated when analyzing (ꢁ)-1, the respective minor
enantiomers in the HPLC of both (þ)- and (ꢀ)-1 were not detected. This is due to the insufficient
resolution (RS ¼ 1.2), and positive ꢃnonlinear effectsꢄ [47] are ruled out. Hence, we adopt the
reliable ee-values from the starting (þ)- and (ꢀ)-11.

Helvetica Chimica Acta – Vol. 93 (2010)
1295
chloride (6 mg, 0.026 mmol) was added at r.t. and kept for 1 h. CC (SiO2; CH2Cl2) and recrystallization
(hexane/Et2O) gave 14 (12 mg, 95%). Colorless tablets. M.p. 96 – 978. Rf (hexane/Et2O 3 :2) 0.49. IR
(KBr): 3050w, 2993w, 2940m, 2834m, 1787w, 173vs, 1721vs, 1611m, 1589s, 151vs, 1483m, 1451m, 1441m,
1418w, 1398m, 1388m, 1369w, 1301m, 1267vs, 1243vs, 1194vs, 1167s, 1073w, 1049w, 1033w, 1010w, 979w,
955w, 925w, 902w, 876m, 845m, 833m, 814s, 767m, 751s, 707w, 681w, 637w, 628w, 598w, 572w, 553w, 529w,
491w, 475w. 1H-NMR (400 MHz, CDCl3): 8.06, 7.65 (AA’BB’, 3J ¼ 8.7, 4-BrC6H4); 7.32 (AA’ of AA’BB’,
3J ¼ 8.5, HꢀC(2’), HꢀC(6’)); 7.24 (AA’ of AA’BB’, 3J ¼ 8.6, HꢀC(2’’’), HꢀC(6’’’)); 7.10 (BB’ of AA’BB’,
3J ¼ 8.6, HꢀC(3’’’), HꢀC(5’’’)); 6.89 (BB’ of AA’BB’, 3J ¼ 8.5, HꢀC(3’), HꢀC(5’)); 4.31 (dd, 3J(2,3ax) ¼
11.1, 3J(2,3eq) ¼ 2.0, HꢀC(2)); 3.81 (s, MeOꢀC(4’)); 3.47 (dddd, 3J(5ax,6) ¼ 10.9, 3J(5eq,6) ¼ 1.9,
2
3
3J(1’’,6) ꢄ 7, 4, HꢀC(6)); 2.78 (m, ddt-like, J ¼ 14.0, J ꢄ 9, 6, CH2(2’’)); 1.94 (m, w1/2 ꢄ 22, HꢀC(1’’),
HeqꢀC(4)); 1.80 (m, w1/2 ꢄ 35, HꢀC(1’’), HeqꢀC(3)); 1.66 (m, w1/2 ꢄ 25, HaxꢀC(4), HeqꢀC(5)); 1.51 (br.
3
3
3
qd-like, 2J ꢄ J(2,3ax) ꢄ J(3ax,4ax) ꢄ 13, 3J(3ax,4eq) ꢄ 4, HaxꢀC(3)); 1.35 (qd-like, 2J ꢄ J(4ax,5ax) ꢄ
3J(5ax,6) ꢄ 11, J(4eq,5ax) ꢄ 4, HaxꢀC(5)). 13C-NMR (100.6 MHz, CDCl3): 164.6 (CO); 158.7 (C(4’));
3
148.7 (C(4’’’)); 140.4 (C(1’’’)); 135.9 (C(1’)); 131.9 (Co); 131.6 (Cm); 129.3 (C(2’’’), C(6’’’)), 128.7 (Cp);
128.6 (Cipso); 127.1 (C(2’), C(6’)), 121.2 (C(3’’’), C(5’’’)); 113.6 (C(3’), C(5’)); 79.1 (C(2)); 77.0 (C(6)); 55.3
(MeOꢀC(4’)); 38.0 (C(1’’)); 33.4 (C(3)); 31.3 (C(5)); 31.1 (C(2’’)); 24.0 (C(4)). EI-MS: 496, 494 (34, 33,
M(81Br)þ, M(79Br)þ, C27H27BrO4þ ), 218 (9), 191 (5), 185 (97, 81BrC6H6COþ), 183 (100, 79BrC6H6COþ),
174 (14), 157 (8, [185 ꢀ CO]þ), 155 (9, [183 ꢀ CO]þ), 150 (6), 148 (9), 147 (22), 137 (11), 136 (7), 135
(17), 134 (12), 121 (25, C8H9Oþ), 107 (11, C7H7Oþ), 105 (6), 104 (7), 91 (6, PhCHþ2 ), 77 (7).
11. X-Ray Crystal-Structure Determinations of Natural (ꢀ)-Centrolobine ((ꢀ)-1) from Brosimum
potabilis [8] and of 4-Bromobenzoate 14 of Synthetic (ꢀ)-1. The measurements were made on a Nonius-
KappaCCD area-detector diffractometer [48] by using graphite-monochromated MoKa radiation (l
0.71073 ꢆ) and an Oxford-Cryosystems Cryostream-700 cooler. The data collection and refinement
parameters are compiled in the Table, and ORTEP [49] representations of the molecules are shown in
Figs. 4 and 5. Data reduction was performed with HKL DENZO and SCALEPACK [50]. For (ꢀ)-1, the
intensities were corrected for Lorentz and polarization effects but not for absorption. The space group
was uniquely determined by the systematic absences. Equivalent reflections were merged. For 14, the
intensities were corrected for Lorentz and polarization effects, and an absorption correction based on the
multi-scan method [51] was applied. The space group was uniquely determined by the systematic
absences. Equivalent reflections, other than Friedel pairs, were merged.
The structures were solved by direct methods with SIR92 [52], which revealed the positions of all
non-H-atoms. The non-H-atoms were refined anisotropically. The OH H-atom of (ꢀ)-1 was placed in the
position indicated by a difference electron density map, and its position was allowed to refine together
with an isotropic displacement parameter. All remaining H-atoms were placed in geometrically
calculated positions and refined by using a riding model where each H-atom was assigned a fixed
isotropic displacement parameter with a value equal to 1.2 Ueq of its parent C-atom (1.5 Ueq for the Me
group). The refinement of the structure was carried out on F2 by using full-matrix least-squares
procedures, which minimized the function Sw(F2o ꢀ Fc2 )2. The weighting scheme was based on counting
statistics and included a factor to downweight the intense reflections. Plots of Sw(F2o ꢀ Fc2 )2 vs. Fc/Fc
(max) and resolution showed no unusual trends. A correction for secondary extinction was applied. For
14, all of the H-atoms were placed in geometrically calculated positions and refined by using a riding
model where each H-atom was assigned a fixed isotropic displacement parameter with a value equal to
1.2 Ueq of its parent atom (1.5 Ueq for the Me group). The refinement of the structure was carried out on
F2 by using full-matrix least-squares procedures, which minimized the function Sw(Fo2 ꢀ F2c )2. The
weighting scheme was based on counting statistics and included a factor to downweight the intense
reflections. Plots of Sw(F2o ꢀ Fc2 )2 vs. Fc/Fc (max), and resolution showed no unusual trends. A correction
for secondary extinction was applied. One reflection, whose intensity was considered to be an extreme
outlier, was omitted from the final refinement. Refinement of the absolute structure parameter [53]
yielded a value of ꢀ 0.003(6), which confidently confirms that the refined model corresponds with the
true enantiomorph. Neutral-atom scattering factors for non-H-atoms were taken from [54], and the
scattering factors for H-atoms from [55]. Anomalous dispersion effects were included in Fc [56]; the
values for f’ and f’’ were those of [57]. The values of the mass-attenuation coefficients were those of [58].
The SHELXL97 program [59] was used for all calculations.

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Helvetica Chimica Acta – Vol. 93 (2010)
Table. Crystallographic Data of (ꢀ)-1 and 14
(ꢀ)-1
14
Crystallized from
Empirical formula
Mr
hexane/AcOEt
C20H24O3
312.41
hexane/Et2O
C27H27BrO4
495.41
Crystal color, habit
Crystal dimensions [mm]
Temperature [K]
Crystal system
Space group
colorless, prism
0.12 ꢃ 0.15 ꢃ 0.28
160(1)
orthorhombic
P212121 (#19)
4
colorless, tablet
0.12 ꢃ 0.20 ꢃ 0.28
160(1)
orthorhombic
P212121 (#19)
4
Z
Reflections for cell determination
1825
45645
2q Range for cell determination [8]
4 – 50
4 – 55
Unit cell parameters
a [ꢆ]
b [ꢆ]
5.5337(2)
15.3020(5)
20.5737(5)
90
1742.11(9)
672
6.8901(1)
15.8695(3)
21.6135(3)
90
2363.27(6)
1024
1.392
1.775
w
c [ꢆ]
a ¼ b ¼ g [8]
V [ꢆ3]
F(000)
Dx [g cmꢀ3
]
1.191
m(MoKa) [mmꢀ1
Scan type
]
0.0787
f and w
50
2q(max) [8]
55
Transmission factors (min; max)
Total reflections measured
Symmetry-independent reflections
Rint
Reflections with I > 2s(I)
Reflections used in refinement
Parameters refined
0.699; 0.807
39687
5309
0.052
4339
25490
1807
0.081
1522
1807
214
5308
291
Final R(F) (I > 2s(I) reflections)
0.0427
0.1008
)
0.0299
0.0679
)
wR(F2) (all data)
a
b
Weights
Goodness of fit
1.137
1.069
Secondary extinction coefficient
Final Dmax/s
0.106(7)
0.001
0.0054(7)
0.001
D1 (max; min) [e ꢆꢀ3
s(d(CꢀC)) [ꢆ]
]
0.28; ꢀ 0.28
0.24; ꢀ 0.47
0.003 – 0.004
0.003
b
a) w ¼ [s2(F2o ) þ (0.0595P)2]ꢀ1 where P ¼ (Fo2 þ 2Fc2 )/3. ) w ¼ [s2(F2o ) þ (0.0299P)2 þ 0.4876P]ꢀ1 where
P ¼ (F2o þ 2F2c )/3.
REFERENCES
[1] C. Bꢁrgi, P. Rꢁedi, Helv. Chim. Acta 1993, 76, 1890; C. Bꢁrgi, G. Liu, P. Rꢁedi, Helv. Chim. Acta
1993, 76, 1901.
[2] W. Breu, A. Sendl, C. Bꢁrgi, P. Rꢁedi, H. Wagner, Planta Med. 1990, 56, 665.
[3] M. Juch, ꢃIsolierung, Strukturaufklꢀrung und Synthese von optisch aktiven Alkylcatecholen aus
Plectranthus sylvestris (Labiatae) als Inhibitoren der Lipoxygenaseꢄ, Ph.D. Thesis, University of
Zurich 1997; M. Juch, P. Rꢁedi, Helv. Chim. Acta 1997, 80, 421, and refs. cit. therein.

Helvetica Chimica Acta – Vol. 93 (2010)
[4] M. Juch, P. Rꢁedi, Curr. Org. Chem. 1999, 3, 623.
1297
[5] O. GonÅalves da Lima, M. Machado de Albuquerque, M. H. Dalia Maia, Rev. Inst. Antibiot. (Univ.
Recife) 1959, 2, 19.
`
[6] I. L. de Albuquerque, C. Galeffi, C. B. Casinovi, G. B. Marini-Bettolo, Gazz. Chim. Ital. 1964, 94,
287.
`
[7] C. Galeffi, C. G. Casinovi, G. B. Marini-Bettolo, Gazz. Chim. Ital. 1965, 95, 95.
ˆ
´
[8] A. F. de C. Alcantara, M. R. Souza, D. Pilo-Veloso, Fitoterapia 2000, 71, 613.
˜
[9] A. Aragao Craveiro, A. Da Costa Prado, O. R. Gottlieb, P. C. Welerson de Albuquerque,
Phytochemistry 1970, 9, 1869.
[10] L. Jurd, R. Y. Wong, Aust. J. Chem. 1984, 37, 1127.
[11] L. V. Alegrio, R. Braz-Filho, O. R. Gottlieb, Phytochemistry 1989, 28, 2359.
[12] S. Ohta, M. Koyama, T. Aoki, T. Suga, Bull. Chem. Soc. Jpn. 1985, 58, 2423.
[13] M. Nagai, N. Kenmochi, M. Fujita, N. Furukawa, T. Inoue, Chem. Pharm. Bull. 1986, 34, 1056.
´
´
[14] G. M. Keserꢁ, M. Nogradi, ꢃThe Chemistry of Natural Diarylheptanoids. In Studies in Natural
Products Chemistryꢄ, Ed. Atta-ur-Rahman, Elsevier Science B. V., New York, 1995, Vol. 17,
pp. 357 – 394.
[15] V. Bçhrsch, S. Blechert, J. Chem. Soc., Chem. Commun. 2006, 1968.
[16] P. A. Clarke, S. Santos, Eur. J. Org. Chem. 2006, 2045.
´
˜
˜
[17] F. Colobert, R. Des Mazery, G. Solladie, M. C. Carreno, Org. Lett. 2002, 4, 1723; M. C. Carreno, R.
´
Des Mazery, A. Urbano, F. Colobert, G. Solladie, J. Org. Chem. 2003, 68, 7779.
[18] S. Marumoto, J. J. Jaber, J. P. Vitale, S. D. Rychnovsky, Org. Lett. 2002, 4, 3919.
[19] K.-P. Chan, T.-P. Loh, Org. Lett. 2005, 7, 4491; G. Sabita, K. B. Reddy, G. S. K. K. Reddy, N. Fatima,
J. S. Yadav, Synlett 2005, 15, 2347; C.-H. A. Lee, T.-P. Loh, Tetrahedron Lett. 2006, 47, 1641; M. Pham,
A. Allatabakhsh, T. G. Minehan, J. Org. Chem. 2008, 73, 741; M. Dziedzic, B. Furman, Tetrahedron
Lett. 2008, 49, 678.
[20] P. A. Evans, J. Cui, S. J. Gharpure, Org. Lett. 2003, 5, 3883.
`
[21] L. Boulard, S. BouzBouz, J. Cossy, X. Franck, B. Figadere, Tetrahedron Lett. 2004, 45, 6603.
[22] M. P. Jennings, R. T. Clemens, Tetrahedron Lett. 2005, 46, 2021.
[23] D. K. Mohapatra, R. Pal, H. Rahaman, M. K. Gurjar, Heterocycles 2010, 80, 219.
[24] P. A. Clarke, W. H. C. Martin, Tetrahedron Lett. 2004, 45, 9061; P. A. Clarke, W. H. C. Martin,
Tetrahedron 2005, 61, 5433.
[25] S. Chandrasekhar, S. J. Prakash, T. Shyamsunder, Tetrahedron Lett. 2005, 46, 6651.
[26] K. Prasad, P. Anbarasan, Tetrahedron 2007, 63, 1089.
[27] T. Washio, R. Yamaguchi, T. Abe, H. Nambu, M. Ananda, S. Hashimoto, Tetrahedron 2007, 63, 12037.
[28] W. Chazadaj, R. Kowalczyk, J. Jurczak, J. Org. Chem. 2010, 75, 1740.
[29] T. Takeuchi, M. Matsuhashi, T. Nakata, Tetrahedron Lett. 2008, 49, 6462.
[30] A. He, N. Sutivisedsak, C. D. Spilling, Org. Lett. 2009, 11, 3124.
[31] M. S. Ali, Y. Tetsuka, A. H. Banskota, S. Kadota, J. Nat. Prod. 2001, 64, 491; M. S. Ali, A. H.
Banskota, Y. Tetsuka, I. Saiki, S. Kadota, Biol. Pharm. Bull. 2001, 24, 525.
[32] J. K. Prasain, J.-X. Li, Y. Tezuka, K. Tanaka, P. Basnet, H. Dong, T. Namba, S. Kadota, Planta Med.
1999, 65, 196.
[33] J. K. Prasain, Y. Tezuka, J.-X. Li, K. Tanaka, P. Basnet, H. Dong, T. Namba, S. Kadota, Planta Med.
2000, 66, 590.
[34] C. R. Reddy, P. P. Madavi, S. Chandrasekhar, Synthesis 2008, 18, 2939.
[35] B. Schmidt, F. Hçlter, Chem. – Eur. J. 2009, 15, 11948.
[36] F. Rogano, ꢃBiomimetische Totalsynthese von enantiomerenreinen 2,6-disubstituierten Tetrahy-
dropyranenꢄ, Ph.D. Thesis, University of Zurich, 2009.
[37] F. Rogano, G. S. Froidevaux, P. Rꢁedi, Helv. Chim. Acta 2010, 93, 1299.
[38] G. S. Froidevaux, ꢃ Herstellung der isomeren Methoxycentrolobole und Zyklisierung zu iso-
Centrolobin. Ein Beitrag zur Strukturaufklꢀrung von Centrolobin aus Centrolobium robustumꢄ,
M.Sc. Thesis, University of Zurich, 2001.
[39] G. E. Keck, E. P. Boden, Tetrahedron Lett. 1984, 25, 265; G. E. Keck, K. H. Tarbet, L. S. Geraci, J.
Am. Chem. Soc. 1993, 115, 8467; G. E. Keck, D. Krishnamurthy, Org. Synth. 1998, 75, 12.

1298
Helvetica Chimica Acta – Vol. 93 (2010)
[40] J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 1969, 34, 2543; G. R. Sullivan, J. A. Dale, H. S.
Mosher, J. Org. Chem. 1973, 38, 2143; J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512; I.
Ohtani, T. Kusumi, Y. Kahman, H. Kakisawa, J. Am. Chem. Soc. 1991, 113, 4092.
[41] J. S. Kingsbury, J. P. A. Harrity, P. J. Bonitatebus Jr., A. H. Hoveyda, J. Am. Chem. Soc. 1999, 121,
791; S. B. Garber, J. S. Kingsbury, A. H. Hoveyda, J. Am. Chem. Soc. 2000, 122, 8186.
[42] Y. Oikawa, K. Horita, O. Yonemitsu, Heterocycles 1985, 23, 553; L. M. Harwood, J. Robertson,
Tetrahedron Lett. 1987, 28, 5175.
[43] M. Nagai, M. Kubo, M. Fujita, T. Inoue, M. Matsuo, Chem. Pharm. Bull. 1978, 26, 2805.
[44] M. Kubo, T. Inoue, M. Nagai, Chem. Pharm. Bull. 1980, 28, 3000.
[45] P. Henley-Smith, D. A. Whiting, A. F. Wood, J. Chem. Soc., Perkin Trans. 1 1980, 614; R. C. Ronald,
C. J. Wheeler, J. Org. Chem. 1984, 49, 1658.
´
´
[46] E. Falomir, P. Alvarez-Bercedo, M. Carda, J. A. Marco, Tetrahedron Lett. 2005, 46, 8407; P. Alvarez-
Bercedo, E. Falomir, M. Carda, J. A. Marco, Tetrahedron 2006, 62, 9641.
[47] C. Puchot, O. Samuel, E. Dunach, S. Zhao, C. Agami, H. B. Kagan, J. Am. Chem. Soc. 1986, 108,
2353.
[48] R. Hooft, KappaCCD Collect Software, Nonius BV, Delft, The Netherlands, 1999.
[49] C. K. Johnson, ORTEPII, Report ORNL-5138, Oak Ridge National Laboratory, Oak Ridge,
Tennessee, 1976.
[50] Z. Otwinowski, W. Minor, in ꢃMethods in Enzymology, Vol. 276, Macromolecular Crystallographyꢄ,
Part A, Eds. C. W. Carter Jr., R. M. Sweet, Academic Press, New York, 1997, p. 307.
[51] R. H. Blessing, Acta Crystallogr., Sect A 1995, 51, 33.
[52] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla, G. Polidori, M. Camalli,
SIR92, J. Appl. Crystallogr. 1994, 27, 435.
[53] H. D. Flack, G. Bernardinelli, Acta Crystallogr., Sect A 1999, 55, 908; H. D. Flack, G. Bernardinelli, J.
Appl. Crystallogr. 2000, 33, 1143.
[54] E. N. Maslen, A. G. Fox, M. A. OꢄKeefe, in ꢃInternational Tables for Crystallographyꢄ, Ed. A. J. C.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, p. 477.
[55] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem. Phys. 1965, 42, 3175.
[56] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 781.
[57] D. C. Creagh, W. J. McAuley, in ꢃInternational Tables for Crystallographyꢄ, Ed. A. J. C. Wilson,
Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 4.2.6.8, p. 219.
[58] D. C. Creagh, J. H. Hubbell, in ꢃInternational Tables for Crystallographyꢄ, Ed. A. J. C. Wilson,
Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 4.2.4.3, p. 200.
[59] G. M. Sheldrick, SHELXL97, Program for the Refinement of Crystal Structures, University of
Gçttingen, Germany, 1997.
Received March 10, 2010