The biomimetic synthesis and first characterization of the (+)- and (-)-isocentrolobines, 2,6-cis- and 2,6-trans-disubstituted tetrahydro-2H-pyrans

Article abstract of DOI:10.1002/hlca.201000097

The four stereoisomers of the novel title compounds were prepared by oxidative cyclization of their enantiomerically pure diarylheptanoid precursors by means of the straightforward biomimetic approach presented in the preceding article. The isocentrolobin

Full text of DOI:10.1002/hlca.201000097

Helvetica Chimica Acta – Vol. 93 (2010)
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The Biomimetic Synthesis and First Characterization of the (þ)- and
(ꢀ)-Isocentrolobines, 2,6-cis- and 2,6-trans-Disubstituted Tetrahydro-2H-
pyrans
by Frank Rogano, Georges Froidevaux, 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 four stereoisomers of the novel title compounds were prepared by oxidative cyclization of their
enantiomerically pure diarylheptanoid precursors by means of the straightforward biomimetic approach
presented in the preceding article. The isocentrolobines are the methoxy regioisomers of the natural (þ)-
and (ꢀ)-centrolobines and were characterized for the first time. The synthetic procedure established the
absolute configurations and the unambiguous correlation with the chiroptical data. The spectroscopic
and the chiroptical data of the isocentrolobines are highly similar to those of the natural products. The
single diagnostic parameter that would allow a immediate assignment in the presence of only one of the
isomers is the higher melting point (ca. 508) of the cis-configured isocentrolobines.
1. Introduction. – In the preceding article, we described the synthesis and final
structure determination of the natural 2,6-cis-disubstituted tetrahydro-2H-pyrans (þ)-
and (ꢀ)-centrolobine [1]. The key step of the procedure was the oxidative cyclization of
the enantiomerically pure diarylheptanoid precursors with retention of their absolute
configuration. As such, it constitutes a straightforward biomimetic approach and
enables the access to the hitherto unknown isocentrolobine series by appropriate
selection of the aryl substituents (Scheme 1) [1 – 3]. In this report, we present the first
preparation and characterization of the four isocentrolobine stereoisomers i.e., of (þ)-
and (ꢀ)-1 (cis) and (þ)- and (ꢀ)-12 (trans), where the OH and the MeO groups are
interchanged with respect to the natural products.
2. Synthesis and Characterization of the (þ)- and (ꢀ)-Isocentrolobines. – 2.1. (þ)-
(S)- and (ꢀ)-(R)-O-Methylisocentrolobol ((þ)- and (ꢀ)-11, resp.). Following the
general protocol [1], the precursors (þ)- and (ꢀ)-11 were obtained from the homoallyl
alcohols (þ)- and (ꢀ)-7 by cross-metathesis with 1-(benzyloxy)-4-(prop-2-en-1-
yl)benzene (6; obtained from 4 via 5), and catalytic hydrogenation of the resulting
diarylheptanoids (þ)- and (ꢀ)-10 (Scheme 2): Enantioselective allylation of aldehyde 3
(obtained from 2) under Keck conditions [4] yielded (þ)-(R)- and (ꢀ)-(S)-7 (ee > 99%
and > 98%, resp.). The absolute configurations were verified by means of the
respective O-MTPA derivatives [5] 8 and 9 and proved to be as expected [4] (MTPA ¼
methoxy(phenyl)(trifluoromethyl)acetyl1). Treating (þ)- and (ꢀ)-7 with 6 in the
1
)
As in [1], this additional verification was performed to exclude further potential errors.
ꢂ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Scheme 1
presence of Hoveyda – Grubbs (2nd gen.) catalyst HG-II [6] at ꢀ 7882) furnished the
diarylheptanoid homoallyl alcohols (þ)- and (ꢀ)-10 ((E)/(Z) ca. 10 :1), and hydro-
genation afforded the (þ)-(S)- and (ꢀ)-(R)-O-methylisocentrolobols (þ)- and (ꢀ)-11
(ee > 99% and > 98%, resp.).
2.2. Isocentrolobines (þ)- and (ꢀ)-1 and (þ)- and (ꢀ)-12. Like in the synthesis of the
natural centrolobines [1], the key step is the oxidative cyclization of the O-
methylisocentrolobols (þ)- and (ꢀ)-11 (Schemes 2 and 3): Treatment of (þ)-11 with
DDQ and chromatographic separation afforded the isocentrolobine (þ)-1 (36%; ee
> 99%) as the main compound besides the minor trans-configured 2-epimer (ꢀ)-12
(8%; ee > 99%). Analogously, cyclization of (ꢀ)-11 furnished (ꢀ)-1 (34%; ee > 98%)
and its 2-epimer (þ)-12 (8%; ee > 99%). Similar to [1], ca. 40% of the precursors (þ)-
and (ꢀ)-11 could be recycled. Finally, the molecular structures of (ꢀ)-1 and (þ)-12
were confirmed by X-ray crystallographic analyses (Figs. 1 and 2)3). Compared to the
results in the natural centrolobine series [1], the yields of the cyclization reaction were
significantly higher. This is due to the position of the easily oxidizable phenolic OH
group in the O-methylisocentrolobols (þ)- and (ꢀ)-11 that facilitates the formation of
the intermediate quinone methide 11ox and precludes the side reaction via 11ox’ to the
oxetane 13 (Scheme 3). This interpretation is consistent with the findings in [1], where
the cyclization of the O-methylcentrolobols resulted in decomposition and had to be
enforced after protection of the OH group. As expected, the sterically most favorable
diequatorial arrangement of the substituents in 11ox leads to the 2,6-cis-isomers (þ)-
and (ꢀ)-1 as the main products. However, the less favored axial – equatorial arrange-
2
)
As discussed in [1], the metathesis reaction succeeded only when the glassware was soaked in 10%
HCl solution during 16 h before use and when the reaction was performed at ꢀ 788 (see Exper. Part
(General) in [1]).
The full data set is summarized in the Table (see Exper. Part). CCDC-765629 and -765630 contain
the supplementary crystallographic data for (ꢀ)-1 and (þ)-12. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_
request/cif.
3
)

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Scheme 2
a) DIBAH (diisobutylaluminium hydride), CH2Cl2, ꢀ 788. b) BnBr, NaH, THF, reflux. c) Mg, I2, THF,
reflux. d) CH2¼CHCH2Br, THF, ꢀ 58. e) (ꢀ)-(S)-[1,1’-Binaphthalene]-2,2’-diol/(iPrO)4Ti, CH2Cl2,
reflux. f) CH2¼CHCH2SnBu3, ꢀ 788 !ꢀ 208. g) (þ)-(R)-[1,1’-Binaphthalene]-2,2’-diol/(iPrO)4Ti,
CH2Cl2, reflux. h) (ꢀ)-(R)-MTPA-Cl, DMAP (N,N-dimethylpyridin-4-amine), Et3N, r.t. i) 6,
Hoveyda – Grubbs (2nd gen.) catalyst HG-II, CH2Cl2, ꢀ 788 ! r.t. j) H2, 10% Pd/C, CH2Cl2, r.t.
k) DDQ (4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile), AcOH, CH2Cl2, ꢀ 208. l) CC
(SiO2, hexane/CH2Cl2/AcOEt).

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ment is also passed, thus affording the respective 2,6-trans-isomers (þ)- and (ꢀ)-12 as
minor components (Scheme 3)4).
Scheme 3
2.3. Absolute Configurations and Chiroptical Data. Since the configuration at C(3)
of the precursors (þ)-(S)- and (ꢀ)-(R)-11 is retained after the oxidative cyclization, the
absolute configuration at C(6) of the resulting 2,6-disubstituted tetrahydro-2H-pyrans
is preassigned. The one at C(2) follows from the relative 2,6-cis- or 2,6-trans-
arrangement that is easily established by 1H-NMR spectroscopy. As a consequence, the
structures of the novel isocentrolobines are assigned: (þ)-(2R,6S)-1, (ꢀ)-(2S,6R)-1,
(þ)-(2R,6R)-12, and (ꢀ)-(2S,6S)-12. Compared to the natural 2,6-cis-configured
centrolobines ((þ)-(2R,6S) and (ꢀ)-(2S,6R), resp.), the sign of the optical rotations
remains unchanged, and their values are almost equal in the 2,6-cis-configured
isocentrolobines. However, the sign of the optical rotations is opposite in the
corresponding trans-series, a finding that is consistent with the synthetic trans-
4
)
Although not discussed in [1], we assume that the corresponding trans-centrolobines are also
formed after cyclization of the O-methylcentrolobols. However, due to the low yields (<10%), they
were not detected.

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Fig. 1. Molecular structure of synthetic (ꢀ)-isocentrolobine ((ꢀ)-1). For reasons of clarity, the atom
numbering is restricted to the tetrahydro-2H-pyran moiety; 50% probability ellipsoids.
Fig. 2. Molecular structure of the synthetic (þ)-trans-isocentrolobine ((þ)-12). For reasons of clarity, the
atom numbering is restricted to the tetrahydro-2H-pyran moiety; 50% probability ellipsoids.
centrolobines (¼epi-centrolobines, (þ)-(2R,6R) and (ꢀ)-(2S,6S), resp.) [7]. Hence, it
can be concluded that the aryl substituent at the stereogenic center C(2) determines the
chiroptical data5).
5
)
See the discussion in [1] concerning the very probably erroneous assignment [8] of a natural trans-
centrolobine congener.

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3. Differentiation between Centrolobines and Isocentrolobines. – As discussed in
[1], the structure of the natural centrolobines had been established only ambiguously
[9]. Although the respective isocentrolobines were neither known nor taken into
consideration, it was anticipated by implication that the two isomers would significantly
differ in the physical, in particular the spectral data. In fact, just the melting points and
the chromatographic behavior of the regioisomers are apparently different: (þ)- and
(ꢀ)-1 have a m.p. 145 – 1468 and Rf (SiO2, hexane/Et2O 1:2) 0.42, and the (þ)- and (ꢀ)-
centrolobines have a m.p. 93 – 948 and Rf (SiO2, hexane/Et2O 1:2) 0.20 [1]. In contrast,
both the 2,6-cis-configured isocentrolobines and their centrolobine counterparts
display highly similar IR, NMR, and mass spectra. Differences are only noticeable
when a direct comparison of both isomers is made (Fig. 3). Whereas the IR (Fig. 3,a)
and the 13C-NMR spectra (Fig. 3,c) are nearly identical, the aromatic region in the
1H-NMR exhibits features that would allow to distinguish the two regioisomers from
each other (Fig. 3,b): The chemical-shift differences are significantly smaller in the
isocentrolobines (þ)- and (ꢀ)-1, and the signals are more compressed ((Dd ¼
d(HꢀC(2’,6’)) ꢀ d(HꢀC(2’’’,6’’’)) ¼ 0.15, and Dd¼ d(HꢀC(3’,5’)) ꢀ d(HꢀC(3’’’,5’’’))6)
¼ 0.04, see Exper. Part) than those of the centrolobines (Dd ¼ d(HꢀC(2’,6’)) ꢀ
d(HꢀC(2’’’,6’’’)) ¼ 0.29, and Dd ¼ d(HꢀC(3’,5’)) ꢀ d(HꢀC(3’’’,5’’’))6) ¼ 0.19 [1]). Al-
though the chromatographic behavior and the 1H-NMR data would suggest to allow a
determination in the presence of only one of the isomers, the single reliable diagnostic
parameter is the melting point. Since its difference (ca. 508) is adequate, it constitutes
an absolute parameter that is not dependent on extrinsic experimental factors.
However, this conclusion can only be made in retrospect, with both regioisomers on
hand.
4. Remarks. – Owing to the first description of the isocentrolobines and the review
of the centrolobines [1], all eight stereoisomers of these 2-phenyl-6-(phenylethyl)-
substituted tetrahydro-2H-pyrans are now fully characterized7). The comparison of the
spectral and chiroptical data clearly demonstrates that an assignment with respect to
one of the regioisomeric series is virtually meaningless as long as the alternative
structure is not known nor even considered. This holds also for antiquated physical
parameters like melting points as long as one is unaware of the alternative. It is
remarkable that the melting point is the only straightforward diagnostic value that
permits an unambiguous determination8). These considerations may lead to the
assumption that the O-methylisocentrolobols (þ)- and (ꢀ)-119) as well as the
isocentrolobines (þ)- and (ꢀ)-1 arguably are genuine natural products that have been
6
)
)
For the atom numbering, see Fig. 4 (Exper. Part).
7
The 2,6-trans-configured centrolobines (¼epi-centrolobines, (þ)-(2R,6R) and (ꢀ)-(2S,6S), resp.)
have already been prepared [7].
8
)
)
Actually, less importance is attached to antiquated parameters, and sophisticated spectroscopic
methods are predominant. This report illustrates an example where spectroscopy alone is
unreliable.
A racemic compound with the constitution of O-methylisocentrolobol, i.e., (ꢁ)-11, was reported to
be a degradation product of acerogenin B. But only its O-methyl derivative was characterized and
found to be identical with the known (ꢁ)-di-O-methylcentrolobol [10].
9

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Fig. 3. Spectral comparison of (ꢀ)-isocentrolobine ((ꢀ)-1) (top traces) and (ꢀ)-centrolobine (bottom
traces). a) IR Spectra (CHCl3), b) 1H-NMR spectra (600 MHz, CDCl3), and c) 13C-NMR spectra
(150.9 MHz, CDCl3).

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ignored due to the similarity with the known isomers. However, no such evidence was
discovered10), and the statement remains speculative.
The authors 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. See [1]. Nomenclature and atom numbering: Similar to [1], the arbitrary atom numbering
is used for the description of the compounds. Hence, the C-atoms in the centrolobine series [1] maintain
their numbers in the isocentrolobine series to facilitate a straightforward spectral comparison (Fig. 4);
systematic names are given in the headings.
Fig. 4. Arbitrary atom numbering for the diarylheptanes and the tetrahydro-2H-pyrans
2. 3-(4-Methoxyphenyl)propanal (¼4-Methoxybenzenepropanal; 3). Reduction of methyl 3-(4-
methoxyphenyl)propanoate (¼ methyl 4-methoxybenzenepropanoate; 2; 5.0 g, 25.74 mmol; prepared
from 4-methoxycinnamic acid (purum, Fluka 6542) by standard procedures) in anh. CH2Cl2 (90 ml) with
1M diisobutylaluminium hydride (DIBAH; 26 ml, 26.0 mmol in CH2Cl2) at ꢀ 808, workup, and CC
(SiO2; hexane/AcOEt 9 :1) yielded 3 (3.67 g 87%). Colorless oil. Rf (hexane/Et2O 1:2) 0.45. GC (ꢃlowꢄ):
tR 7 min 9 s. IR (film): 3032w, 3002w, 2935m, 2835m, 1723vs, 1611m, 1583w, 1513vs, 1465m, 1442m, 1407w,
1388w, 1357w, 1300m, 1247vs, 1179s, 1111w, 1034s, 860w, 830m, 812m, 769w, 663w, 542m. 1H-NMR
3
3
(300 MHz, CDCl3): 9.81 (t, J ¼ 1.5, HꢀC(1)); 7.11 (AA’ of AA’BB’, J ¼ 8.7, HꢀC(2’), HꢀC(6’)); 6.83
(BB’ of AA’BB’, 3J ¼ 8.7, HꢀC(3’), HꢀC(5’)); 3.78 (s, MeOꢀC(4’)); 2.91 (t, 3J(3,2) ¼ 7.4, CH2(3)); 2.75
(tt, 3J (2,3) ¼ 7.5, 3J(1,2) ¼ 1.5, CH2(2)). 13C-NMR (75.4 MHz, CDCl3): 201.7 (C(1)); 158.1 (C(4’)); 132.3
(C(1’)); 129.2 (C(2’), C(6’)); 114.0 (C(3’), C(5’)); 55.3 (MeOꢀC(4’)); 45.5 (C(2)); 27.3 (s, C(3)). EI-MS:
166 (41, Mþ), 135 (4), 121 (100, C8H9Oþ), 119 (3), 108 (33), 105 (4), 103 (5), 91 (17, PhCHþ2 ), 89 (4), 79
(5), 77 (19), 65 (11), 63 (7), 55 (3), 51 (9).
3. 1-(Benzyloxy)-4-(prop-2-en-1-yl)benzene (¼1-(Phenylmethoxy)-4-(prop-2-en-1-yl)benzene; 6).
To a suspension of NaH (6.5 g, 159 mmol) in anh. THF (50 ml), 4-bromophenol (4; 20.0 g, 115.6 mmol)
was added at 08 and stirred at r.t. (30 min). Then benzyl bromide (17 ml, 143.2 mmol) was added, and the
mixture kept under reflux (18 h). Workup, CC (SiO2; hexane ! hexane/AcOEt 99 :1), and recrystal-
lization (hexane/Et2O) afforded 1-(benzyloxy)-4-bromobenzene (¼1-bromo-4-(phenylmethoxy)ben-
zene; 5; 25.24 g, 83%). Colorless needles. M.p. 63 – 648. Rf (hexane/Et2O 5 :2) 0.54. GC (ꢃlowꢄ): tR 10 min
25 s. IR (KBr): 3088w, 3061m, 1638w, 1587m, 1576s, 1487vs, 1452s, 1404m, 1378m, 1335w, 1312m, 1289s,
1248vs, 1170s, 1117m, 1103m, 1080m, 1070m, 1042s, 1026s, 999m, 931m, 905m, 825vs, 813s, 734vs, 694s,
657m, 562w, 532w, 505m, 462w. 1H-NMR (300 MHz, CDCl3): 7.44 – 7.30 (m and AA’ of AA’BB, 3J ¼ 9.0,
PhCH2, HꢀC(2), HꢀC(6)); 6.86 (BB’ of AA’BB’, 3J ¼ 9.0, HꢀC(3), HꢀC(5)); 5.04 (s, PhCH2).
10
)
The most recent report on the isolation of (ꢀ)-centrolobine ([a]D ¼ ꢀ92.2) from the heartwood of
Brosimum potabile (Moraceae) [11] might have been such a candidate. The constituent was
identified and characterized by 1H- and 13C-NMR spectroscopy, but the m.p. is not reported. In our
hands, the authentic sample had m.p. 87 – 908, and the X-ray crystallographic analysis confirmed the
proposed structure [1]. However, the formula depicted for (ꢀ)-centrolobine [11] represents the (þ)-
enantiomer.

Helvetica Chimica Acta – Vol. 93 (2010)
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13C-NMR (75.4 MHz, CDCl3): 157.9 (C(4)); 136.6 (PhCH2); 132.3 (C(2), C(6)); 128.6, 128.1, 127.4
(PhCH2); 116.7 (C(3), C(5)); 113.1 (C(1)); 70.2 (PhCH2)). EI-MS: 264, 262 (8, 8, M(81Br)þ, M(79Br)þ,
C13H11BrOþ), 173 (2, [M(81Br) ꢀ PhCH2]þ), 171 (2, [M(79Br) ꢀ PhCH2]þ), 157 (1), 155 (1), 154 (1), 152
(1), 145 (5), 143 (5), 119 (2), 117 (2), 91 (100, PhCHþ2 ), 89 (6), 77 (3), 65 (30), 63 (18), 51 (7).
To a refluxing suspension of Mg turnings (1.40 g, 57.6 mmol) and an I2 crystal in anh. THF, a soln. of 5
(15.0 g, 57.0 mmol) in anh. THF (120 ml) was slowly added and kept for 3 h under reflux. After cooling to
ꢀ 58, a soln. of allyl bromide (5 ml, 59.13 mmol) in anh. THF (15 ml) was added and the mixture stirred
at r.t. (18 h). Workup, CC (SiO2; hexane/AcOEt 99 :1) and bulb-to-bulb distillation at 1008/10ꢀ3 mbar
afforded 6 (10.82 g, 85%). Colorless oil. Rf (hexane/Et2O 5 :2) 0.58. GC (ꢃlowꢄ): tR 10 min 12 s. IR (film):
3065m, 3032m, 3005m, 2977m, 2901m, 1638m, 1611s, 1583m, 1509vs, 1454s, 1433m, 1381s, 1298s, 1241vs,
1175vs, 1112m, 1080w, 1025w, 995w, 913vs, 860m, 830m, 816m, 783m, 735s, 696s, 646m, 592w, 576w, 527m,
455w. 1H-NMR (300 MHz, CDCl3): 7.48 – 7.32 (m, PhCH2); 7.14 (AA’ of AA’BB’, 3J ¼ 8.7, HꢀC(3),
HꢀC(5)); 6.95 (BB’ of AA’BB’, 3J ¼ 8.7, HꢀC(2), HꢀC(6)); 5.96 (ddt, 3J ¼ 16.8, 10.4, 6.7, HꢀC(2’)); 5.08
3
2
4
3
2
4
(dq, J ¼ 16.8 , J ꢂ J ꢂ 1.5, HtransꢀC(3’)); 5.07 (dq, J ¼ 10.4, J ꢂ J ꢂ 1.5, HcisꢀC(3’)); 5.06 (s, PhCH2);
3.35 (br. d, 3J ¼ 6.7, CH2(1’’)). 13C-NMR (75.4 MHz, CDCl3): 157.2 (C(1)); 137.8 (C(2’)); 137.2 (PhCH2);
132.4 (C(4’)); 129.5 (C(3), C(5)); 128.5, 127.8, 127.4 (PhCH2); 115.4 (C(3’)); 114.8 (C(2), C(6)); 70.1
(PhCH2); 39.3 (C(1’)). EI-MS: 224 (16, Mþ), 181 (1), 133 (1, [M ꢀ PhCH2]þ), 115 (2), 105 (2), 103 (3), 91
(100, PhCHþ2 ), 89 (3), 79 (3), 78 (4), 77 (8), 65 (21), 63 (5), 53 (2), 51 (7).
4. (þ)-(3R)- and (ꢀ)-(3S)-1-(4-Methoxyphenyl)hex-5-en-3-ol (¼(þ)-(aR)- and (ꢀ)-(aS)-4-Me-
thoxy-a-prop-2-en-1-yl)benzenepropanol, resp.; (þ)- and (ꢀ)-7, resp.)11). Following the protocol in [1],
we obtained from 3 (2.00 g, 12.18 mmol), after treatment with (ꢀ)-(S)-[1,1’-binaphthalene]-2,2’-diol
(349 mg, 1.22 mmol), (iPrO)4Ti (360 ml, 1.22 mmol), and CH2¼CHCH2SnBu3 (4.5 ml, 14.7 mmol) and
CC (SiO2; hexane/Et2O 2 :1), (þ)-7 (2.01 g, 80%; ee > 99%) as colorless oil that solidified in the
refrigerator. Analogously, starting from 3 (2.00 g, 12.18 mmol), (þ)-(R)-[1,1’-binaphthalene]-2,2’-diol
(350 mg, 1.22 mmol), (iPrO)4Ti (360 ml, 1.22 mmol), and CH2¼CHCH2SnBu3 (4.5 ml, 14.7 mmol), we
obtained (ꢀ)-7 (2.11 g, 84%; ee > 98%). HPLC (Chiralcelꢀ OD-H, hexane/iPrOH 50 :1): k’((þ)-7) ¼ 3.6,
k’((ꢀ)-7) ¼ 2.9, RS ¼ 3.6).
Data of (þ)-7: M.p. 39 – 408. Rf (hexane/Et2O 1:2) 0.38. GC (ꢃlowꢄ): tR 9 min 2 s. [a]D ¼ þ19.6 (c ¼
0.56, EtOH). IR (KBr): 3352s, 3283s, 3103w, 3071m, 3032w, 3001m, 2944m, 2917s, 2862m, 2838m, 1642m,
1612m, 1586w, 1513vs, 1468m, 1453m, 1362w, 1334w, 1322w, 1300m, 1274m, 1244vs, 1179s, 1164m, 1131w,
1109m, 1081s, 1062m, 1036vs, 988m, 952w, 938w, 912m, 867m, 820s, 766m, 751m, 717s, 662m, 629m, 560m,
533m, 509w. 1H-NMR (400 MHz, CDCl3): 7.13 (AA’ of AA’BB’, 3J ¼ 8.4, HꢀC(2’), HꢀC(6’)); 6.84 (BB’
of AA’BB’, 3J ¼ 8.6, HꢀC(3’), HꢀC(5’)); 5.82 (X of ABMX, 3J ¼ 17.3, 10.2, 7.8, 5.5, HꢀC(5)); 5.14 (dq-
4
like, 3J ¼ 17.3, 10.2, 2J ꢂ J < 1, CH2(6)); 3.79 (s, MeOꢀC(4’)); 3.70 (M of ABMX, quint.-like, 3J ꢂ 7,
HꢀC(3)); 2.75 (A of ABXY, 2J ¼ 14.3, 3J ¼ 7.2, HAꢀC(1)); 2.64 (B of ABXY, 2J ¼ 14.3, 3J ¼ 7.8,
HBꢀC(1)); 2.32 (A of ABMX, 2J ¼ 14.5, 3J ¼ 5.5, 4J < 1 HAꢀC(4)); 2.18 (B of ABMX, 2J ¼ 14.5, 3J ¼ 7.8,
HBꢀC(4)); 1.76 (XY of ABXY, q-like, CH2(2)); 1.65 (s, HOꢀC(3)). 13C-NMR (100.6 MHz, CDCl3):
157.8 (C(4’)); 134.6 (C(5’)); 134.1 (C(1’)); 129.3 (C(2’), C(6’)); 118.2 (C(6)); 113.8 (C(3’), C(5’)); 69.9
(C(3)); 55.2 (MeOꢀC(4’)); 42.0 (C(2)); 38.6 (C(4)); 31.1 (C(1)). EI-MS: 206 (21, Mþ), 188 (5, [M ꢀ
H2O]þ), 173 (2), 164 (4), 159 (2), 147 (37), 134 (7), 121 (100, C8H9Oþ), 119 (4), 108 (10), 105 (3),
103 (4), 91 (18, PhCHþ2 ), 89 (4), 78 (17), 77 (19), 65 (8), 63 (4), 55 (3), 51 (6).
Data of (ꢀ)-7: [a]D ¼ ꢀ18.4 (c ¼ 0.58, EtOH). All other data: identical with those of (þ)-7.
5. (S)-MTPA Derivatives 8 and 9 for the Confirmation of the Absolute Configuration. Each
homoallyl alcohol (þ)- or (ꢀ)-7 (each 15 mg, 0.073 mmol) was dissolved in anh. CH2Cl2 (1 ml) and Et3N
(20 ml, 0.144 mmol). DMAP (1 mg) and (þ)-(R)-MTPA-Cl (14 ml, 0.075 mmol) were added, and the
mixture was stirred at r.t. for 4 h. Workup and CC (SiO2; hexane/AcOEt 19 :1) afforded the (S)-MTPA
ester 8 (26 mg, 85%) or 9 (27 mg, 88%), resp., both as colorless, viscous oils.
(3R)-1-(4-Methoxyphenyl)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-Methoxyphenyl)ethyl]but-3-en-
1-yl Ester; 8): Rf (hexane/Et2O 1:1) 0.56. GC (ꢃlowꢄ): tR 13 min 34 s. 1H-NMR (400 MHz, CDCl3): 7.60 –
7.57, 7.44 – 7.39 (m, Ph); 7.05 (AA’ of AA’BB’, 3J ¼ 8.7, HꢀC(2’), HꢀC(6’)); 6.83 (BB’ of AA’BB’, 3J ¼ 8.7,
11
)
The compounds have been prepared and well documented earlier: (þ)-7 [12] and (ꢀ)-7 [13].

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Helvetica Chimica Acta – Vol. 93 (2010)
HꢀC(3’), HꢀC(5’)); 5.65 (ddt, 3J ¼ 17, 10, 6, HꢀC(5)); 5.18 (br. quint., 3J ꢂ 6, HꢀC(3)); 5.03 (dq-like,
2
4
5
3J ¼ 17, 10, J ꢂ J ꢂ 1, CH2(6)); 3.79 (s, MeOꢀC(4’)); 3.57 (q, J(H,F) ¼ 1.2, MeO of MTPA); 2.59 (m,
3
4
dquint.-like, w1/2 ꢂ 30, CH2(1)); 2.40 (tt, J ¼ 6, J ꢂ 1, CH2(4)); 1.95 (m, dquint.-like, w1/2 ꢂ 30, CH2(2)).
13C-NMR (100.6 MHz, CDCl3): 166.2 (CO); 158.0 (C(4’)); 133.0 (C(1’)); 132.6 (C(5)); 132.3, 129.6 (Ph);
129.2 (C(2’), C(6’)); 128.4, 127.5 (Ph); 123.4 (q, 1J(C,F) ¼ 289, CF3); 118.5 (s, C(6)); 114.0 (C(3’), C(5’));
2
84.6 (q, J(C,F) ¼ 27.9, PhC(MeO)(CF3)CO); 76.0 (C(3)); 55.4 (MeO of MTPA); 55.3 (MeOꢀC(4’));
38.0 (C(4)); 35.4 (C(2)); 30.6 (C(1)). EI-MS: 422 (4, Mþ), 189 (56, [M ꢀ MTPA ꢀ H2O]þ), 173 (2), 159
(4), 147 (73), 139 (3), 134 (6), 127 (4), 121 (100, C8H9Oþ), 115 (2), 107 (1, C7H7Oþ), 105 (11), 91 (9,
PhCHþ2 ), 77 (8), 69 (2), 51 (1).
(3S)-1-(4-Methoxyphenyl)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-Methoxyphenyl)ethyl]but-3-en-
1-yl Ester; 9): Rf (hexane/Et2O 1:1) 0.56. GC (ꢃlowꢄ): tR 13 min 34 s. 1H-NMR (400 MHz, CDCl3): 7.61 –
7.58, 7.43 – 7.39 (m, Ph); 6.98 (AA’ of AA’BB’, 3J ¼ 8.7, HꢀC(2’), HꢀC(6’)); 6.81 (BB’ of AA’BB’, 3J ¼ 8.7,
HꢀC(3’), HꢀC(5’)); 5.76 (ddt, 3J ¼ 17, 10, 7, HꢀC(5)); 5.18 (br. quint. 3J ꢂ 6, HꢀC(3)); 5.12 (dq, 3J ¼ 17,
4
4
2J ꢂ J ꢂ 1, HtransꢀC(6)); 5.11 (dq, 3J ¼ 10, 2J ꢂ J ꢂ 1, HcisꢀC(6)); 3.78 (s, MeOꢀC(4’)); 3.59 (q,
5J(H,F) ¼ 1.3, MeO of MTPA); 2.46 (br. sext.-like, w1/2 ꢂ 20, CH2(1), CH2(4)); 1.88 (br. tq-like, w1/2 ꢂ 15,
CH2(2)). 13C-NMR (100.6 MHz, CDCl3): 166.2 (CO); 158.0 (C(4’)); 133.1 (C(1’)); 132.9 (C(5)); 132.4,
129.6 (Ph); 129.2 (C(2’), C(6’)); 128.4, 127.4 (Ph); 123.4 (q, 1J(C,F) ¼ 289, CF3); 118.6 (C(6)); 113.9
2
(C(3’), C(5’)); 84.5 (q, J(C,F) ¼ 27.5, PhC(MeO)(CF3)CO); 75.9 (C(3)); 55.5 (MeO of MTPA); 55.2
(MeOꢀC(4’)); 38.3 (C(4)); 35.4 (C(2)); 30.26 (C(1)). EI-MS: 422 (3, Mþ), 189 (55, [M ꢀ MTPA ꢀ
H2O]þ), 173 (2), 159 (3), 147 (75), 139 (4), 134 (6), 127 (4), 121 (100, C8H9Oþ), 115 (2), 107 (1,
C7H7Oþ), 105 (12), 91 (9, PhCHþ2 ), 77 (9), 69 (2), 51 (1).
Dd(1H) ¼ d(S) ꢀ d(R) ¼ d(9) ꢀ d(8) (in Hz): CH2(1) ꢀ 52, CH2(2) ꢀ 28, HꢀC(3) 0, CH2(4) ꢀ 24,
HꢀC(5) þ 44, and CH2(6) þ 34. The relative displacements [5] confirm the expected [4] absolute
configuration at C(3).
5. (þ)- and (ꢀ)-(5E)-4’’-O-(Benzyloxy)-5,6-didehydro-4’-O-methylisocentrolobol (¼(þ)-(3R,5E)-
and (ꢀ)-(3S,5E)-7-[4-(Benzyloxy)phenyl]-1-(4-methoxyphenyl)hept-5-en-3-ol ¼ (þ)-(aR)- and (ꢀ)-
(aS)-a-{(2E)-4-[4-(Phenylmethoxy)phenyl]but-2-en-1-yl}-4-methoxybenzenepropanol, resp.; (þ)- and
(ꢀ)-10, resp.). To a soln. of catalyst HG-II (42 mg, 0.067 mmol) in anh. CH2Cl2 (4.5 ml) at ꢀ 788, a soln.
of (þ)-7 (150 mg, 0.73 mmol) and 1-(benzyloxy)-4-(prop-2-en-1-yl)benzene (6; 657 mg, 2.93 mmol) in
anh. CH2Cl2 (3 ml) was slowly added under Ar. The mixture was stirred (1 h) at ꢀ 788, allowed to warm
to r.t. for 6 h, then quickly passed through SiO2 (hexane/CH2Cl2/AcOEt 2 :7:1) and concentrated. CC
(SiO2; hexane/CH2Cl2/AcOEt 5 :14 :1) afforded starting (þ)-7 (58 mg, 39%) that could be recycled, and
(þ)-10 (131 mg, 45%; (E)/(Z) ca. 10 :112) as colorless oil that solidified in the refrigerator. Analogously,
starting from (ꢀ)-7 (150 mg, 0.73 mmol), 6 (655 mg, 2.93 mmol) in anh. CH2Cl2 (7.5 ml), and catalyst
HG-II (44 mg, 0.07 mmol), we obtained (ꢀ)-6 (47 mg, 31%) and (ꢀ)-10 (139 mg, 48%; (E)/(Z) ca.
10 :112).
Data of (þ)-10: M.p. 46 – 498. Rf (hexane/Et2O 1:2) 0.34. [a]D ¼ þ10.2 (c ¼ 0.52, EtOH). IR (KBr):
3354m, 3062w, 3032w, 2999w, 2925m, 2858m, 2832m, 1611m, 1584m, 1510vs, 1465m, 1454m, 1440m,
1429m, 1380m, 1300m, 1244vs, 1176m, 1110w, 1096w, 1074m, 1039s, 1027m, 970m, 921w, 861w, 818m,
1
807m, 737m, 716w, 697m, 623w, 580w, 519w. H-NMR (400 MHz, CDCl3)13): 7.47 – 7.33 (m, Ph); 7.13 (2
3
3
AA’ of AA’BB’, t-like, J ꢂ 9, HꢀC(2’), HꢀC(2’’), HꢀC(6’), HꢀC(6’’)); 6.94 (BB’ of AA’BB’, J ¼ 8.4,
HꢀC(3’’), HꢀC(5’’)); 6.87 (BB’ of AA’BB’, 3J ¼ 8.4, HꢀC(3’’), HꢀC(5’’)); 5.72 (X of ABMX, dt,
3J(5,6) ¼ 14.6, 3J(6,7) ¼ 6.8, HꢀC(6)); 5.52 (br. dt, 3J(5,6) ¼ 14.5, 3J(4,5) ¼ 7.2, 4J(3,5) < 1, HꢀC(5)); 5.07
(s, PhCH2); 3.81 (s, MeOꢀC(4’)); 3.67 (M of ABMX, quint.-like, 3J ꢂ 7, H ꢀC(3)); 3.34 (d, 3J(6,7) ¼ 6.8,
CH2(7)); 2.76 (A of ABXY, 2J ¼ 14.3, 3J ¼ 6.4, HAꢀC(1)); 2.67 (B of ABXY, 2J ¼ 14.3, 3J ¼ 7.7, HBꢀC(1));
2.30 (A of ABMX, 2J ¼ 13.5, 3J ¼ 5.5, 4J < 1 HAꢀC(4)); 2.20 (B of ABMX, 2J ¼ 14.5, 3J ¼ 7.6, HBꢀC(4));
1.77 (XY of ABXY, m, w1/2 ꢂ 15, CH2(2)). 13C-NMR (100.6 MHz, CDCl3)13): 157.7 (C(4’)); 157.1 (C(4’’));
137.1 (Ph); 134.1 (C(1’)); 133.3 (C(6)); 132.8 (C(1’’)); 129.3, 129.2 (C(2’), C(2’), C(6’), C(6’’)); 128.5,
127.8, 127.4 (Ph); 126.9 (C(5)); 114.8 (C(3’’), C(5’’)); 113.8 (C(3’), C(5’)); 70.2 (C(3)); 70.0 (PhCH2); 55.2
1
12
13
)
)
Estimated according to the intensities of the H-NMR signals of CH2(7).
Only the (E)-isomer is specified.

Helvetica Chimica Acta – Vol. 93 (2010)
1309
(MeOꢀC(4’)); 40.7 (C(4)); 38.6 (C(2)); 38.2 (C(7)); 31.0 (C(1)). EI-MS: 402 (7, Mþ), 384 (2, [M ꢀ
H2O]þ), 238 (4), 211 (15), 197 (5), 164 (5), 147 (14), 121 (54, C8H9Oþ), 107 (6, C7H7Oþ), 91 (100,
PhCHþ2 ), 77 (5), 65 (5).
Data of (ꢀ)-10: [a]D ¼ ꢀ8.9 (c ¼ 0.61, CHCl3). All other data: identical with those of (þ)-10.
6. (þ)- and (ꢀ)-4’-O-Methylisocentrolobols (¼(þ)-4-[(5S)- and (ꢀ)-4-[(5R)-5-Hydroxy-7-(4-
methoxyphenyl)heptyl]phenol ¼ (þ)-(aS)- and (ꢀ)-(aR)-a-[2-(4-Methoxyphenyl)ethyl]-4-hydroxyben-
zenepentanol, resp.; (þ)- and (ꢀ)-11, resp.). Following the protocol in [1], hydrogenation of (þ)-10
(250 mg, 0.622 mmol) over 10% Pd/C (45 mg, 0.0343 mmol) and CC (SiO2; hexane/CH2Cl2/AcOEt/
iPrOH 20 :75 :4 :1) afforded (þ)-11 (172 mg, 88%; ee > 99%) as a colorless, viscous oil. Analogously,
starting from (ꢀ)-10 (230 mg, 0.572 mmol) and 10% Pd/C (40 mg, 0.038 mmol), we obtained (ꢀ)-11
(162 mg, 90%; ee > 98%). HPLC (Chiralcelꢀ OD-H, hexane/iPrOH 8 :1): k’((þ)-11) ¼ 8.7, k’((ꢀ)-11) ¼
6.9, RS ¼ 2.5.
Data of (þ)-11: Rf (hexane/Et2O 1:4) 0.45. [a]D ¼ þ8.8 (c ¼ 0.53, EtOH). IR (film): 3356s, 3012m,
2934vs, 1612s, 1513vs, 1454s, 1371m, 1300m, 1245vs, 1178s, 1109w, 1076m, 1035s, 984w, 913w, 827s, 769w,
1
3
747w, 705w, 639w, 556w, 514w. H-NMR (400 MHz, CDCl3): 7.11 (AA’ of AA’BB’, J ¼ 8.7, HꢀC(2’),
HꢀC(6’)); 7.01 (BB’ of AA’BB’, 3J ¼ 8.5, HꢀC(2’’), HꢀC(6’’)); 6.84 (AA’ of AA’BB’, 3J ¼ 8.7, HꢀC(3’),
HꢀC(5’)); 6.75 (BB’ of AA’BB’, 3J ¼ 8.5, HꢀC(3’’), HꢀC(5’’)); 6.00 (br. s, HOꢀC(4’’)); 3.79 (s,
3
3
2
MeOꢀC(4’)); 3.64 (br. quint.-like, J ꢂ 7, H ꢀC(3)); 2,53 (d, J ¼ 6.8, CH2(7)); 2.76 (A of ABXY, J ¼
14.0, 3J ¼ 6.4, HAꢀC(1)); 2.67 (B of ABXY, 2J ¼ 14.0, 3J ¼ 7.0, HBꢀC(1)); 1.74 (XY of ABXY, m, w1/2
ꢂ
25, CH2(2)); 1.58 (m, w1/2 ꢂ 20, CH2(6)); 1.54 – 1.42 (m, CH2(4), HꢀC(5), HOꢀC(3)); 1.36 (m, br. t-
like, w1/2 ꢂ 15, HꢀC(5)). 13C-NMR (100.6 MHz, CDCl3): 157.7 (C(4’)); 153.8 (C(4’’)); 134.3 (C(1’’));
134.1 (C(1’)); 129.3 (C(3’’), C(5’’)), 129.2 (C(3’), C(5’)); 115.1 (C(2’’), C(6’’)); 113.8 (C(2’), C(6’)); 71.5
(C(3)); 55.2 (MeOꢀC(4’)); 39.1 (C(2)); 37.2 (C(4)); 34.9 (C(7)); 31.6 (C(6)); 31.0 (C(1)); 25.1 (C(5)).
EI-MS: 314 (9, Mþ), 296 (17, [M ꢀ H2O]þ), 188 (5), 175 (3), 161 (3), 147 (34), 134 (17), 121 (100,
C8H9Oþ), 107 (36, C7H7Oþ), 91 (8, PhCHþ2 ), 77 (8), 59 (7).
Data of (ꢀ)-11: [a]D ¼ ꢀ8.5 (c ¼ 0.56, EtOH). All other data: identical with those of (þ)-11.
7. Cyclization to the cis- and trans-Tetrahydro-2H-pyrans. (þ)- and (ꢀ)-Isocentrolobine (¼(þ)-
(2R,6S)- and (ꢀ)-(2S,6R)-2-(4-Hydroxyphenyl)-6-[2-(4-methoxyphenyl)ethyl]tetrahydro-2H-pyran ¼
(þ)-4-{(2S,6R)- and (ꢀ)-4-{(2R,6S)-6-[2-(4-Methoxyphenyl)ethyl]tetrahydro-2H-pyran-2-yl}phenol ¼
(þ)-4-{(2S,6R)- and (ꢀ)-4-{(2R,6S)-Tetrahydro-6-[2-(4-methoxyphenyl)ethyl]-2H-pyran-2-yl}phenol,
resp.; (þ)- and (ꢀ)-1, resp.) and (þ)- and (ꢀ)-epi-Isocentrolobine ( ¼ (þ)-(2R,6R)- and (ꢀ)-(2S,6S)-2-
(4-Hydroxyphenyl)-6-[2-(4-methoxyphenyl)ethyl]tetrahydro-2H-pyran, resp.; (þ)- and (ꢀ)-12, resp.). To
a cooled (ꢀ108) soln. of (þ)-11 (25 mg, 0.08 mmol) in anh. CH2Cl2 (6 ml), AcOH (20 ml) and DDQ
(19 mg, 0.084 mmol) were added in a single portion and stirred (5 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) and recrystallization (hexane/Et2O or hexane/AcOEt) afforded (þ)-1 (9 mg,
14
36%; ee > 99% ), (ꢀ)-12 (2 mg, 8%; ee > 99%) both as colorless prisms, and starting (þ)-11 (11 mg,
44%) that could be recycled. Analogously, starting from (ꢀ)-11 (24 mg, 0.076 mmol) and DDQ (18 mg,
0.079 mmol), we obtained (ꢀ)-1 (8 mg, 34%; ee > 98%)14), (þ)-12 (2 mg, 8%; ee > 99%), and starting
(ꢀ)-11 (10 mg, 42%). HPLC (cis; Chiralcelꢀ OD-H, hexane/iPrOH 30 :1): k’((þ)-1) ¼ 6.1, k’((ꢀ)-1) ¼ 5.5,
RS ¼ 1.15 (not sufficient for a reliable ee-determination)14). HPLC (trans; Chiralcelꢀ OD-H, hexane/
iPrOH 15 :1): k’(ꢀ)-12) ¼ 3.45, k’((þ)-12) ¼ 6.4, RS ¼ 7.1.
Data of (þ)-1: M.p. 145 – 1468. Rf (hexane/Et2O 1:2) 0.42. GC (ꢃhighꢄ): tR 16 min 2 s. [a]D ¼ þ90.3
(c ¼ 0.7, CHCl3). IR (KBr): 3350s, 3063m, 3009m, 2943s, 2918s, 2894m, 2838s, 1614s, 1584m, 1511vs, 1456s,
1442vs, 1388m, 1366m, 1347m, 1310m, 1289m, 1269s, 1243vs, 1224vs, 1181vs, 1174s, 1124m, 1085w, 1072m,
1043vs, 1020vs, 980m, 955m, 938m, 920m, 898m, 863m, 837s, 828vs, 821vs, 809s, 784m, 755w, 742m, 719w,
616m, 575m, 540w, 524m, 511m, 458w. 1H-NMR (600 MHz, CDCl3): 7.26 (AA’ of AA’BB’, 3J ¼ 8.5,
HꢀC(2’), HꢀC(6’)); 7.11 (AA’ of AA’BB’, 3J ¼ 8.7, HꢀC(2’’’), HꢀC(6’’’)); 6.82 (BB’ of AA’BB’, 3J ¼ 8.7,
14
)
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 1.15), and positive ꢃnonlinear effectsꢄ [14] are ruled out. Hence, we adopt the
reliable ee-values from the starting (þ)- and (ꢀ)-11.

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Helvetica Chimica Acta – Vol. 93 (2010)
HꢀC(3’’’), HꢀC(5’’’)); 6.78 (BB’ of AA’BB’, 3J ¼ 8.5, HꢀC(3’), HꢀC(5’)); 4.88 (s, HOꢀC(4’)); 4.29 (dd,
3J(2,3ax) ¼ 11.1, 3J(2,3eq) ¼ 2.0, HꢀC(2)); 3.79 (s, MeOꢀC(4’’’)); 3.46 (dddd, 3J(5ax,6) ¼ 9.8,
3
2
3
3
3J(5eq,6)¼ 1.8, J(1’’,6)ꢂ 7, 5, HꢀC(6)); 2.71 (ddt-like, J ¼ 14.0, J ꢂ 9, Jꢂ 6, CH2(2’’)); 1.91 (m, w1/2
ꢂ
25, HꢀC(1’’), HeqꢀC(4)); 1.83 (br. dq-like, 2J ꢂ 11, 3J(2,3eq) ꢂ J(3eq,4ax) ꢂ J(3eq,4eq) ꢂ 2,
3
3
HeqꢀC(3)); 1.74 m, w1/2 ꢂ 25, HꢀC(1’’)); 1.63 (qt-like, 2J ꢂ J(3ax,4ax) ꢂ J(4ax,5ax) ꢂ 11,
3
3
3J(3ax,4eq) ꢂ J(4eq, 5ax) ꢂ 3, HaxꢀC(4)); 1.63 (br. dq-like, 2J ꢂ 11, 3J(4ax,5eq) ꢂ J(4eq,5eq) ꢂ
3
3
3J(5eq,6) ꢂ 2, HeqꢀC(5)); 1.51 (qd-like, 2J ꢂ J(2,3ax) ꢂ J(3ax,4ax) ꢂ 11, 3J(3ax,4eq) ꢂ 2, HaxꢀC(3));
3
3
1.33 (qd-like, 2J ꢂ J(4ax,5ax) ꢂ J(5ax,6) ꢂ 11, 3J(4eq,5ax) ꢂ 3, HaxꢀC(5)). 13C-NMR (150.9 MHz,
CDCl3): 157.6 (C(4’’’)); 154.7 (C(4’)); 135.9 (C(1’’’)); 134.6 (C(1’)); 129.4 (C(2’’’), C(6’’’)); 127.3 (C(2’),
C(6’)); 115.0 (C(3’), C(5’)); 113.7 (C(3’’’), C(5’’’)); 79.1 (C(2)); 77.2 (C(6)); 55.3 (MeOꢀC(4’’’)); 38.3
(C(1’’)); 33.2 (C(3)); 31.2 (C(5)); 30.7 (C(2’’)); 24.0 (C(4)). EI-MS: 312 (9, Mþ), 281 (4, [M ꢀ MeO]þ),
207 (14), 191 (2), 177 (3), 174 (3), 163 (15), 160 (12), 147 (7), 134 (14), 133 (15), 121 (100, C8H9Oþ), 119
(6), 107 (15, C7H7Oþ), 91 (12, PhCH2þ ), 79 (4), 77 (12), 73 (3), 65 (7), 55 (5), 51 (3).
3
3
Data of (ꢀ)-1: [a]D ¼ ꢀ89.1 (c ¼ 0.6, CHCl3). All other data: identical with those of (þ)-1.
Data of (þ)-12: M.p. 130 – 1318. Rf (hexane/Et2O 1:2) 0.37. GC (ꢃhighꢄ): tR 16 min 11 s. [a]D ꢂ 0;
[a]435 ¼ þ6.7 (c ¼ 0.23, CHCl3). IR (KBr): 3250s, 3034m, 2999m, 2941vs, 2859m, 2835m, 1612vs, 1593m,
1512vs, 1443vs, 1385w, 1345s, 1324m, 1302m, 1263vs, 1245vs, 1214vs, 1174vs, 1149m, 1115m, 1089m,
1071m, 1058m, 1032vs, 1019vs, 976m, 959w, 931m, 920m, 873m, 854m, 838vs, 825vs, 771m, 718m, 657w,
639w, 576w, 553m, 527w, 505m, 480w. 1H-NMR (600 MHz, CDCl3): 7.27 (AA’ of AA’BB’, 3J ¼ 8.4,
HꢀC(2’), HꢀC(6’)); 7.11 (AA’ of AA’BB’, 3J ¼ 8.6, HꢀC(2’’’), HꢀC(6’’’)); 6.82 (BB’ of AA’BB’, 3J ¼ 8.6,
HꢀC(3’’’), HꢀC(5’’’)); 6.81 (AA’ of AA’BB’, 3J ¼ 8.4, HꢀC(3’), HꢀC(5’)); 4.80 (br. s, HOꢀC(4’)); 4.78
(t, 3J(2,3ax) ¼ 3J(2,3eq) ¼ 5.4, HꢀC(2)); 3.79 (s, MeOꢀC(4’’’)); 3.77 (sext.-like, 3J(5ax,6) ¼ 11.0,
3
2
3
3
2
3J(5eq,6) ꢂ J(6,1’’) ꢂ 5, HꢀC(6)); 2.76, 2.57 (each ddd, J ¼ 12, J ¼ 8, J ¼ 5, CH2(2’’)); 2.08 (ddt, J ¼
3
3
3
14, J ¼ 9, J ¼ 5, HꢀC(1’’)); 1.90 (q, J ¼ 5.7, CH2(3)); 1.79 – 1.64 (m, HꢀC(1’’), CH2(4’’), HeqꢀC(5));
1.46 (m, br. dq-like, w1/2 ꢂ 20, HaxꢀC(5)). 13C-NMR (150.9 MHz, CDCl3): 157.7 (C(4’’’)); 154.5 (C(4’));
134.6 (C(1’)); 134.5 (C(1’’’)); 129.3 (C(2’’’), C(6’’’)); 128.0 (C(2’), C(6’)); 115.1 (C(3’), C(5’)); 113.7
(C(3’’’), C(5’’’)); 71.8 (C(2)); 71.3 (C(6)); 55.3 (MeOꢀC(4’’’)); 35.2 (C(1’’)); 31.3 (C(2’’)); 30.2 (C(3));
29.9 (C(5)); 19.0 (C(4)). EI-MS: 312 (8, Mþ), 281 (6, [M ꢀ MeO]þ), 253 (2), 207 (15), 191 (2), 173 (2),
163 (18), 160 (12), 147 (8), 134 (14), 133 (18), 121 (100, C8H9Oþ), 115 (4), 108 (5), 107 (13, C7H7Oþ), 105
(4), 103 (4), 93 (5), 91 (14, PhCHþ2 ), 81 (2), 79 (3), 77 (13), 73 (4), 65 (7), 55 (8), 51 (3).
Data of (ꢀ)-12: [a]D ꢂ 0; [a]435 ¼ ꢀ6.6 (c ¼ 0.2, CHCl3). All other data: identical with those of (þ)-
12.
8. X-Ray Crystal-Structure Determinations of (ꢀ)-1 and (þ)-12. The measurements were made on a
Nonius-KappaCCD area-detector diffractometer [15] by using graphite-monochromated MoKa radia-
tion (l 0.71073 ꢅ) and an Oxford-Cryosystems-Cryostream-700 cooler. The data collection and
refinement parameters are compiled in the Table, and ORTEP [16] representations of the molecules
are shown in Figs. 1 and 2. Data reduction was performed with HKL DENZO and SCALEPACK [17].
The intensities were corrected for Lorentz and polarization effects but not for absorption. For (ꢀ)-1, the
space group was determined from the systematic absences, packing considerations, a statistical analysis of
intensity distribution, and the successful solution and refinement of the structure. Equivalent reflections
were merged. For (þ)-12, the space group was uniquely determined by the systematic absences.
Equivalent reflections were merged. The structures were solved by direct methods with SIR92 [18],
which revealed the positions of all non-H-atoms. The non-H-atoms were refined anisotropically. The OH
H-atom 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 (þ)-12, two reflections, whose intensities were considered to be extreme outliers, were
omitted from the final refinement. Neutral-atom scattering factors for non-H-atoms were taken from

Helvetica Chimica Acta – Vol. 93 (2010)
1311
[19], and the scattering factors for H-atoms from [20]. Anomalous dispersion effects were included in Fc
[21]; the values for f’ and f’’ were those of [22]. The values of the mass-attenuation coefficients were
those of [23]. The SHELXL97 program [24] was used for all calculations.
Table. Crystallographic Data of (ꢀ)-1 and (þ)-12
(ꢀ)-1
(þ)-12
Crystallized from
Empirical formula
Mr
hexane/Et2O
C20H24O3
312.41
hexane/AcOEt
C20H24O3
312.41
Crystal color, habit
Crystal dimensions [mm]
Temperature [K]
colorless, prism
0.20 ꢃ 0.22 ꢃ 0.25
160(1)
colorless, prism
0.15 ꢃ 0.17 ꢃ 0.17
160(1)
Crystal system
Space group
Z
monoclinic
P21 (#4)
2
orthorhombic
P212121 (#19)
4
Reflections for cell determination
2598
1825
2q Range for cell determination [8]
4 – 60
4 – 50
Unit cell parameters:
a [ꢅ]
b [ꢅ]
c [ꢅ]
8.6423(2)
5.6418(2)
17.3530(3)
90
6.9496(2)
8.2301(3)
30.6091(9)
90
a [8]
b [8]
103.103(2)
90
824.07(4)
336
1.259
0.0830
w
90
90
g [8]
V [ꢅ3]
F(000)
1750.7(1)
672
1.185
0.0781
f and w
50
Dx [g cmꢀ3
]
m(MoKa) [mmꢀ1
Scan type
]
2q(max) [8]
60
Total reflections measured
Symmetry independent reflections
Rint
Reflections with I > 2s(I)
Reflections used in refinement
Parameters refined; restraints
Final R(F) (I > 2s(I) reflections)
wR(F2) (all data)
27230
2615
0.057
2149
2615
17402
1820
0.082
1399
1818
214
214; 1
0.0463
0.1124
0.0490
0.1057
a
b
Weights
)
)
Goodness of fit
1.042
1.103
Secondary extinction coefficient
Final Dmax/s
0.030(6)
0.001
0.023(2)
0.001
D1 (max; min) [e ꢅꢀ3
s(d(CꢀC)) [ꢅ]
]
0.25; ꢀ 0.19
0.17; ꢀ 0.16
0.002 – 0.003
0.004 – 0.005
a) w ¼ [s2(F2o ) þ (0.0581P)2 þ 0.1052P]ꢀ1 where P ¼ (F2o þ 2Fc2 )/3. b) w ¼ [s2(F2o ) þ (0.0331P)2 þ
0.5084P]ꢀ1 where P ¼ (Fo2 þ 2Fc2 )/3.

1312
Helvetica Chimica Acta – Vol. 93 (2010)
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Received March 10, 2010