A stereodivergent synthesis of all stereoisomers of centrolobine: Control of selectivity by a protecting-group manipulation

Article abstract of DOI:10.1002/chem.200902053

All stereoisomers of the natural product centrolobine are selectively synthesized, by starting from a common precursor. Key steps are an enantioselective allylation with enantiomerically pure allylsilanes, a tandem ring-closing metathesis-isomerization re

Full text of DOI:10.1002/chem.200902053

DOI: 10.1002/chem.200902053
A Stereodivergent Synthesis of All Stereoisomers of Centrolobine: Control of
Selectivity by a Protecting-Group Manipulation
Bernd Schmidt* and Frank Hçlter[a]
Dedicated to the memory of Professor Wolfgang Kreiser
Abstract: All stereoisomers of the natural product centrolobine are selectively syn-
thesized, by starting from a common precursor. Key steps are an enantioselective
Keywords:
diazonium salts · Heck reaction ·
isomerization · metathesis
allylation
·
allylation with enantiomerically pure allylsilanes, a tandem ring-closing metathe-
sis–isomerization reaction, and a Heck reaction by using an arene diazonium salt.
By choosing appropriate conditions for the final deprotection step, either the cis-
configured centrolobines or their epimers are selectively obtained.
Introduction
In evolutionary biology, the term sympatry describes the
phenomenon that closely related biological species occur in
the same or overlapping geographical regions. Sympatry is
normally associated with chemical diversity of the metabo-
lites produced by these species, which is most likely essential
for the coexistence of closely related species in one area.[1]
From a chemistꢀs point of view, the selective formation of
stereoisomeric metabolites by sympatric species is particu-
larly interesting. For instance, the laevorotatory (3R,7S)-
(ꢀ)-centrolobine ((3R,7S)-1) was isolated from the heart-
wood of the tree Centrolobium tomentosum,[2] whereas its
enantiomer (3S,7R)-(+)-centrolobine ((3S,7R)-1) occurs in
the closely related species Centrolobium robustum
(Scheme 1).[3,4] Both enantiomers have antibiotic and anti-
fungal activity, which suggests that these compounds play a
role in the plants own pest control mechanism.[2]
Over the past ten years a considerable number of other
natural products with the underlying structural pattern of
the cyclic diarylheptanoids[5] were isolated from various
plants. In several cases, not only the cis-, but also the trans-
configured compounds were isolated and structurally char-
Scheme 1. Structures of representative cyclic diaryl heptanoids and num-
bering scheme.
acterized. Examples are the dihydropyrans (3S,7R)- and
(3S,7S)-2 from Alpinia blepharocalyx[6] and the diospongi-
nes A (cis-configured) and B (trans-configured) from Dio-
scorea spongiosa.[7]
The interesting biological properties of cyclic diarylhepta-
noids stimulated numerous synthetic studies, inter alia, the
enantioselective solid-phase synthesis of a library of com-
pounds.[8,9] Total synthesis became particularly important for
the centrolobines, because it led to a revision of the original
assignment of the absolute configuration in 2002.[10]
[a] Prof. Dr. B. Schmidt, Dipl.-Chem. F. Hçlter
Institut fꢁr Chemie, Professur fꢁr Organische Synthesechemie
Universitꢂt Potsdam, Karl-Liebknecht-Straße 24–25
14476 Golm (Germany)
Fax : (+49)331-977-5059
E-mail: bernd.schmidt@uni-potsdam.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902053.
11948
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11948 – 11953

FULL PAPER
Since then, further enantioselective syntheses were pub-
lished by using various key steps,[11] such as [4+2] cycloaddi-
tion,[12] cross-metathesis with a reductive etherification,[13,14]
a Prins cyclization,[15,16] and a diastereoselective ring rear-
rangement metathesis.[17,18]
In contrast to the 5,6-dehydro-4’’-de-O-methylcentrolo-
bines (2) from Alpinia blepharocalyx, no trans-configured
epimers of the centrolobines have been isolated from natu-
ral sources so far. The interesting stereochemical diversity
observed for natural products with a cyclic diarylheptanoid
structure and their promising biological activities led us to
the development of a stereodivergent route, which is exem-
plified in this contribution for the synthesis of all four ste-
reoisomers of centrolobine.
major advantage of the reagents (R,R)- and (S,S)-4, derived
from C2-symmetric 1,2-cyclohexanediamine, relative to the
alternative reagent derived from pseudoephedrine, is the
convenient access to both enantiomers. Thus, by using
(R,R)-4, the homoallylic alcohol (R)-5 was obtained, where-
as (S,S)-4 gave the enantiomer (S)-5[13] in good yield and
with excellent enantioselectivity. The enantiomeric ratio was
determined to be >98:2 by using Mosherꢀs method:[21] in
1
the H NMR spectrum of the Mosher esters derived from
rac-5, the signals for the AB system of the TBS-protected
phenols are baseline separated. Both enantiomers were ana-
lyzed independently, and in both cases no signals originating
from the opposite enantiomer could be detected in the
1H NMR spectrum. The same result was obtained when
using 19F NMR spectroscopy, in which the signals of the two
Mosher esters of rac-5 are also baseline separated. O-allyla-
tion of the homoallylic alcohols 5 under standard conditions
gave the allyl ethers (R)- and (S)-6, respectively, which were
converted to the cyclic enol ethers 7 by using the tandem
ring-closing metathesis (RCM)–isomerization reaction,
which was developed by Snapper et al.[22] and by us.[23–25]
Results and Discussion
The starting point of the synthesis was the enantioselective
allylation of tert-butyl dimethylsilyl (TBS)-protected alde-
hyde 3[19] by using Leightonꢀs method (Scheme 2).[20]
A
Scheme 2. Stereodivergent route to all stereoisomers of centrolobine: a) (S,S)-4 (1.2 equiv), CH2Cl2, ꢀ158C, (72%, er>98:2); b) (R,R)-4 (1.2 equiv),
CH2Cl2, ꢀ158C, (72%, er>98:2); c) NaH, THF, 658C; then allyl bromide 658C (75%); d) A (5 mol%), toluene, 2-propanol/NaOH, 1108C (93%);
e) PdACHTUNGTRENNUNG(OAc)2 (5 mol%), NaOAc (3 equiv), CH3CN, 8 (1.2 equiv) (91%, dr>98:2); f) Pd(OH)2/C (cat.), H2 (1 bar), ethanol (92%); g) [NBu4]F
(1.1 equiv), THF, 08C (98%); h) HCl in methanol (0.1m) (92%). dr=diastereomeric ratio; er=enantiomeric ratio.
Chem. Eur. J. 2009, 15, 11948 – 11953
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11949

B. Schmidt and F. Hçlter
Introduction of the p-methoxy phenyl substituent required
were obtained without noticeable epimerization and without
ꢀ
for the target structures was achieved by using a Heck reac-
cleavage of the benyzlic C7 O bond of the tetrahydropyran
ring.
[26–28]
tion with arene diazonium salt 8
as the arylating agent.
We obtained the products 9 with high trans diastereoselec-
With the TBS-protected tetrahydropyrans 10 we had
reached a second branching point of our divergent synthesis.
Inspired by observations published by Suzuki et al. in the
course of their synthesis of C-aryl glycosides through a O!
C-rearrangement,[31] we assumed that it should be possible
to isomerize the trans-configured tetrahydropyrans to their
cis-configured epimers. Thus, we had to identify conditions
for the final deprotection step that would proceed with pres-
ervation of the kinetically preferred trans configuration. On
the other hand, a second set of conditions was required that
would result in a deprotection with selective and complete
epimerization to the thermodynamically preferred cis prod-
uct. In the particular case of the TBS protecting group,
cleavage can be achieved by using either acids or fluorides
under nonacidic conditions.[32] With tetrabutylammonium
fluoride in THF at 08C a quantitative, epimerization-free
desilylation of (3R,7R)-10 to (+)-epi-centrolobine and of
(3S,7S)-10 to (ꢀ)-epi-centrolobine[33] was achieved. Acidic
conditions were used to induce an epimerization, either par-
allel or consecutive to the desilylation. A suitable reagent is
a solution of HCl in water/methanol. At HCl concentrations
of 10ꢀ2 m, only a ratio of 4:1 of epi-centrolobine to centrolo-
ꢀ
tivity and as single regioisomers, with the C C double bond
exclusively located between carbon atoms 5 and 6 (for the
diarylheptanoid numbering scheme, refer to Scheme 1).
Very recently, Correia et al. reported the formation of mix-
tures of regioisomers for the Heck reaction of 8 with unsub-
stituted 2,3-dihydropyran (B with R=H in Scheme 3).[29]
1
bine was observed after 72 h, by using H NMR spectrosco-
py of the crude reaction mixture. Increasing the concentra-
tion to 10ꢀ1 m in HCl led to a complete desilylation and epi-
merization on a timescale of a few hours. Spectroscopic data
for (+)- and (ꢀ)-centrolobine, including the optical rota-
tions, are in accord with the published data.[4] This proves
that epimerization under acidic conditions affects only the
stereogenic center at C7. This observation is in agreement
with an epimerization mechanism involving a stabilized ben-
zylic carbocation, as outlined in Scheme 4.
Scheme 3. Heck reaction and subsequent double-bond migration.
ꢀ
The formation of isomers with different locations of the C
C double bond is the result of a subsequent olefin isomeri-
ꢀ
zation, which is induced by Pd H species originating from
the syn-b-hydride elimination during the catalytic cycle of
the Heck reaction (step C!D in Scheme 3). Double-bond
ꢀ
migration starts with an insertion of the alkene into the Pd
H bond, giving a new s-alkyl complex E, which might un-
dergo syn-b-H-elimination to give either the starting alkene
D or the isomerized alkene F. Correiaꢀs results are apparent-
ly in contrast to our own observations and results published
previously by us.[27] This prompted us to reproduce these ex-
periments.[30] We found that with the simple 2,3-dihydropyr-
an used by Correia et al. double-bond migration indeed
occurs to a significant extent, but that substituents R in the
a-position efficiently suppress this olefin isomerization. We
propose that the initiating hydropalladation step (D!E) is
strongly disfavored in the presence of substituents R, due to
destabilizing steric interactions between the Pd and R in the
s-alkyl complex E (Scheme 3).
Scheme 4. Mechanism of the epimerization.
ꢀ
It should be possible to functionalize the C5 C6 double
bond in many different ways, which could open up routes to
several analogues. We wanted to achieve a selective hydro-
genation of the double bond. Eventually, good results were
obtained with Pd(OH)2 on charcoal at 1 bar of hydrogen
pressure. Under these conditions, (3R,7R)- and (3S,7S)-10
Conclusion
We describe a synthesis of all stereoisomeric centrolobines,
by starting from a common precursor. The configuration at
11950
www.chemeurj.org
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11948 – 11953

Stereodivergent Synthesis of All Stereoisomers of Centrolobine
FULL PAPER
perature, and allyl bromide (1.90 mL, 2.66 g, 22.0 mmol) was added drop-
wise. The solution was stirred for 12 h, filtered over Celite, evaporated,
and the residue was chromatographed on silica (eluent: cyclohexane/
MTBE 10:1). Compound (S)-6 (3.80 g, 75%) was obtained as a colorless
liquid. [a]2D0 =ꢀ14.8 (c=1.0 in CH2Cl2); IR: n˜ =3077 (w), 2929 (w),
2857(w), 1609 (m), 1509 (s), 1471 (w), 1251 (s), 1076 (m), 911 cmꢀ1 (s);
1H NMR (300 MHz, CDCl3): d=7.03 (d, J=8.5 Hz, 2H), 6.74 (d, J=
8.5 Hz, 2H), 5.93 (dddd, J=5.6, 5.6, 10.3, 17.2 Hz, 1H), 5.83 (dddd, J=
7.1, 7.1, 10.2, 17.2 Hz, 1H), 5.28 (qd, J=1.7, 17.2 Hz, 1H), 5.16 (qd, J=
1.3, 10.3 Hz, 1H), 5.12–4.99 (m, 2H), 4.05 (tdd, J=1.4, 5.7, 12.6 Hz, 1H),
3.95 (tdd, J=1.4, 5.6, 12.6 Hz, 1H), 2.69 (ddd, J=6.6, 9.0, 14.0 Hz, 1H),
2.57 (ddd, J=6.9, 8.7, 13.9 Hz, 1H), 2.32 (ddd, J=1.3, 2.7, 5.5 Hz, 1H),
2.29 (ddd, J=1.2, 2.4, 4.8 Hz, 1H), 1.83–1.71 (m, 2H), 0.98 (s, 9H),
0.18 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=153.6, 135.4, 134.9,
134.8, 129.2, 119.8, 116.9, 116.5, 77.8, 70.0, 38.3, 35.8, 29.7, 25.7, 18.2,
ꢀ4.4 ppm; MS (ESI): m/z: (%): 221 (20), 247 (20), 289 (100), 347 (20);
HRMS (ESI): m/z: calcd for C21H35O2Si+: 347.2406 [M+H]+; found:
347.2424; elemental analysis calcd (%) for C21H34O2Si: C 72.8, H 9.9;
found: C 73.2, H 10.1.
the stereogenic center C3 is established by an enantioselec-
tive allylation by using Leightonꢀs reagent, which gives
access to both the 3S and the 3R series. The configuration at
C7 results from a highly diastereoselective Pd-catalyzed ary-
lation by using an arene diazonium salt. The kinetically pre-
ferred trans product is formed exclusively. For the final de-
protection step, complementary conditions were identified.
Deprotection can either be achieved with preservation of
the relative configuration established in the Pd-catalyzed
step or with complete and selective epimerization at C7 to
the thermodynamically preferred cis products. Extension of
this concept for the stereodivergent synthesis of other cyclic
diaryl heptanoids and their non-natural analogues is current-
ly in progress.
(R)-{4-[3-(Allyloxy)hex-5-enyl]phenoxy}(tert-butyl)dimethylsilane ((R)-
6): The title compound was obtained from (R)-5 (1.00 g, 3.3 mmol) by
Experimental Section
following the procedure described for (S)-6. Yield: 810 mg (70%); [a]D20
=
+14.4 (c=0.8 in CH2Cl2); other analytical data are identical to those ob-
served for (S)-6.
General: All experiments were conducted in dry reaction vessels under
an atmosphere of dry argon. Solvents were purified by standard proce-
dures. 1H NMR spectra were obtained at 300 or 500 MHz in CDCl3 with
CHCl3 (d=7.26 ppm) as an internal standard. Coupling constants are
given in Hz. Signals reported as multiplets (m) with a single chemical
shift value arise from one proton, or a set of chemically equivalent pro-
tons, giving a symmetrical signal with a clear center. Ranges of chemical
shift are given for multiplet signals arising from two or more chemically
inequivalent, overlapping signals. 13C NMR spectra were recorded at 75
or at 125 MHz in CDCl3 with CDCl3 (d=77.0 ppm) as an internal stan-
dard. Whenever peak assignments in the 13C NMR spectra are given,
these are based on H,H- and H,C-correlation spectroscopy. IR spectra
were recorded as films on NaCl or KBr plates. The peak intensities are
defined as strong (s), medium (m), or weak (w). Mass spectra were ob-
tained at 70 eV. Aldehyde 3[13,19] and both enantiomers of Leightonꢀs re-
agent (4)[20] were prepared by following previously published procedures.
Metathesis catalyst A[34] is commercially available and was used without
further purification. Enantiomeric ratios were determined by using
Mosherꢀs method.[21]
(R)-2-[4-(tert-Butyldimethylsilyloxy)phenethyl]-3,4-dihydro-2H-pyran
((R)-7): [RuCAHTUNGRTNE(NNGU Cl2)ACHTNURTGENGN(NU CHPh)ACHTUNGRTEN(NUGN PCy3)2] (A, 120 mg, 5 mol%) was added to a
solution of (S)-6 (1.00 g, 2.9 mmol) in dry and degassed toluene (25 mL).
The solution was heated to 908C for 1 h. After this time, the starting ma-
terial was fully consumed (TLC), and solid NaOH (32 mg, 0.8 mmol) and
2-propanol (3 mL) were added. The mixture was heated to reflux for 2 h
(TLC control), cooled to ambient temperature, and the solvent was
evaporated. The residue was chromatographed on silica (eluent: cyclo-
hexane/MTBE 10:1) to give (R)-7 (860 mg, 93%) as a colorless liquid.
[a]2D0 =ꢀ31.4 (c=0.9 in CH2Cl2); IR: n˜ =2926 (m), 2856 (w), 1650 (m),
1609 (w), 1509 (s), 1251 (s), 1239 (s), 1066 cmꢀ1 (s); 1H NMR (300 MHz,
CDCl3): d=7.05 (d, J=8.6 Hz, 2H), 6.75 (d, J=8.5 Hz, 2H), 6.39 (d, J=
6.2 Hz, 1H), 4.66 (ddd, J=2.7, 4.7, 6.1 Hz, 1H), 3.78 (dddd, J=2.2, 4.6,
7.8, 10.1 Hz, 1H), 2.79–2.56 (m, 2H), 2.13–1.57 (m, 6H), 0.98 (s, 9H),
0.18 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=153.6, 143.8, 134.7,
129.2, 119.9, 100.4, 74.2, 37.1, 30.7, 27.9, 25.7, 19.8, 18.2, ꢀ4.4 ppm; MS
(ESI): m/z: (%): 221 (50), 281 (20), 297 (100), 319 (80); HRMS (ESI):
m/z: calcd for C19H31O2Si+: 319.2069 [M+H]+; found: 319.2078.
(S)-1-[4-(tert-Butyldimethylsilyloxy)phenyl]hex-5-en-3-ol ((S)-5): Alde-
hyde 3 (2.0 g, 7.6 mmol) was added to a solution of (S,S)-4 (4.50 g,
8.1 mmol) in dry and degassed CH2Cl2 (60 mL) at ꢀ108C. The reaction
vessel was stoppered, and stored in a fridge at ꢀ158C for 24 h. After this
time, the reaction was quenched by addition of aqueous HCl (1m,
10 mL) and warmed to ambient temperature. The organic layer was sepa-
rated, and the aqueous layer extracted with CH2Cl2. The combined or-
ganic extracts were dried with MgSO4, filtered, and all volatiles were
evaporated. The residue was purified by column chromatography on
silica (cyclohexane/MTBE 2:1) to yield (S)-5 (1.70 g, 72%). [a]2D3 =ꢀ12.6
(c=0.8 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.05 (d, J=8.6 Hz,
2H), 6.75 (d, J=8.5 Hz, 2H), 5.82 (dddd, J=6.5, 7.9, 9.6, 17.6 Hz, 1H),
5.24–5.06 (m, 2H), 3.66 (m, 1H), 2.79–2.56 (m, 2H), 2.32 (m, 1H), 2.18
(ttd, J=1.0, 7.8, 14.1 Hz, 1H), 1.80–1.70 (m, 2H), 1.60 (m, 1H), 0.98 (s,
9H), 0.19 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=153.6, 134.7,
134.6, 129.2, 119.9, 118.2, 69.9, 42.0, 38.6, 31.2, 25.7, 18.2, ꢀ4.4 ppm; MS
(ESI): m/z: (%): 221 (45), 247 (40), 289 (100), 307 ppm (10); HRMS
(ESI): m/z: calcd for C18H31O2Si+: 307.2093 [M+H]+; found: 307.2116.
(S)-2-[4-(tert-Butyldimethylsilyloxy)phenethyl]-3,4-dihydro-2H-pyran
((S)-7): The title compound was obtained from (R)-6 (170 mg, 0.5 mmol)
by following the procedure described for (R)-7. Yield: 140 mg (89%);
[a]2D0 =+32.7 (c=0.8 in CH2Cl2); other analytical data are identical to
those observed for (R)-7.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
was added to a suspension of (R)-7 (300 mg, 0.9 mmol), diazonium salt 8
(240 mg, 1.1 mmol), and NaOAc (220 mg, 3.7 mmol) in acetonitrile
(10 mL). The reaction mixture was stirred at ambient temperature, until
evolution of gas had ceased (ca. 3 h). Then the solvent was evaporated
and the residue extracted with methyl tert-butyl ether (MTBE). The sus-
pension was filtered over Celite, and all volatiles were evaporated. The
residue was purified by chromatography on silica (eluent: cyclohexane/
MTBE 5:1) to give (3S,7R)-9 (360 mg, 91%) as a colorless liquid. [a]D20
=
+43.0 (c=1.0 in CH2Cl2); IR: n˜ =2928 (w), 2857 (w), 1606 (m), 1508 (s),
1246 (s), 1170 cmꢀ1 (m); 1H NMR (300 MHz, CDCl3): d=7.33 (d, J=
8.7 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 6.60 (d, J=
8.5 Hz, 2H), 6.03 (ddd, 1H, J=2.2, 4.4, 10.3 Hz, 1H), 5.95 (dd, J=2.0,
10.3 Hz, 1H), 5.28 (brs, 1H), 3.87 (s, 3H), 3.47 (dddd, J=3.9, 3.9, 8.8,
8.8 Hz, 1H), 2.61 (ddd, J=5.2, 8.7, 13.7 Hz, 1H), 2.41 (ddd, J=8.2, 8.2,
13.8 Hz, 1H), 2.12–1.95 (m, 2H), 1.80 (dddd, J=5.1, 8.7, 8.7, 13.9 Hz,
1H), 1.65 (dddd, J=3.8, 8.4, 8.4, 12.3 Hz, 1H), 1.01 (s, 9H), 0.20 ppm (s,
6H); 13C NMR (75 MHz, CDCl3): d=159.2, 153.3, 134.7, 133.2, 129.8,
129.3, 127.6, 125.9, 119.6, 113.5, 73.7, 65.7, 55.2, 37.6, 31.1, 30.6, 25.7, 18.1,
(R)-1-[4-(tert-Butyldimethylsilyloxy)phenyl]hex-5-en-3-ol ((R)-5): The
title compound was obtained from (R,R)-4 (4.50 g, 8.1 mmol) and alde-
hyde 3 (2.1 g, 8.0 mmol) by following the procedure described for the en-
antiomer. Yield: 1.80 g (72%); [a]2D3 =+12.9 (c=1.9 in CH2Cl2); other
analytical data are identical to those observed for (S)-5.
(S)-{4-[3-(Allyloxy)hex-5-enyl]phenoxy}(tert-butyl)dimethylsilane ((S)-6):
NaH (60% dispersion in mineral oil, 880 mg, 22.0 mmol) was slowly
added to a solution of (S)-5 (4.50 g, 14.7 mmol) in dry degassed THF
(50 mL) at 08C. The mixture was refluxed for 1 h, cooled to ambient tem-
Chem. Eur. J. 2009, 15, 11948 – 11953
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11951

B. Schmidt and F. Hçlter
ꢀ4.5 ppm; MS (ESI): m/z: (%): 221 (50), 407 (100), 425 (45); HRMS
(ESI): m/z: calcd for C26H37O3Si+: 425.2483 [M+H]+; found: 425.2512.
J=8.5, 2H), 5.22 (s, 1H), 4.32 (dd, J=1.8, 10.7, 1H), 3.81 (s, 3H), 3.47
(m, 1H), 2.81–2.57 (m, 2H), 2.01–1.25 ppm (m, 8H); 13C NMR (75 MHz,
CDCl3): d=158.7, 153.5, 135.8, 134.5, 129.5, 127.1, 115.1, 113.6, 79.1, 77.3,
55.3, 38.2, 33.2, 31.2, 30.7, 24.0 ppm; MS (ESI): m/z: (%): 107 (100), 219
(25), 313 (38); HRMS (ESI): m/z: calcd for C20H25O3+: 313.1804 [M+H]+;
found: 313.1793; elemental analysis calcd (%) for C20H24O3: C 76.9, H
7.7; found: C 76.7, H 8.3.
ACHTUNGTRENNUNG(2R,6S)-2-[(4-tert-Butyldimethylsilyloxy)phenethyl]-6-[4-(methoxy)-
phenyl]-3,6-dihydro-2H-pyran ((3R,7S)-9): The title compound was ob-
tained from (S)-7 (250 mg, 0.8 mmol) by following the procedure de-
scribed for (3S,7R)-9. Yield: 300 mg (90%); [a]2D0 =ꢀ46.5 (c=1.5 in
CH2Cl2); other analytical data are identical to those observed for
(3S,7R)-9.
(+)-Centrolobine ((3S,7R)-1): The title compound was obtained from
(3S7S)-10 (110 mg, 0.3 mmol) by following the procedure described for
(ꢀ)-centrolobin. Yield: 70 mg (86%); [a]2D0 =+84.0 (c=0.5 in CH2Cl2);
other analytical data are identical to those observed for (ꢀ)-centrolobin.
ACHTUNGTRENNUNG(2R,6R)-2-[(4-tert-Butyldimethylsilyloxy)phenethyl]-6-[4-(methoxy)-
phenyl]-3,6-tetrahydro-2H-pyran ((3R,7R)-10): Pd(OH)2/C (20 weight-%
Pd based on dry mass, 10 mg) was added to a solution of (3S,7R)-9
(500 mg, 1.2 mmol) in ethanol (20 mL). The mixture was exposed to an
atmosphere of hydrogen (1 bar) for 12 h whilst stirring. The catalyst was
removed by filtration, the solvent was evaporated, and the residue puri-
fied by chromatography on silica (eluent: hexane/MTBE 1:1) to give
(3R,7R)-10 (460 mg, 92%). [a]2D0 =+7.7 (c=0.4 in CH2Cl2); IR: n˜ =2930
(m), 2857 (w), 1610 (w), 1508 (s), 1245 (s), 1037 cmꢀ1 (m); 1H NMR
(300 MHz, CDCl3): d=7.33 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.5 Hz, 2H),
6.90 (d, J=8.8 Hz, 2H), 6.74 (d, J=8.5 Hz, 2H), 4.81 (t, J=5.3 Hz, 1H),
3.81 (s, 3H), 3.76 (m, 1H), 2.76 (ddd, J=5.2, 10.6, 14.1 Hz, 1H), 2.55
(ddd, J=6.2, 10.3, 13.9 Hz, 1H), 2.09 (dddd, J=5.3, 9.0, 10.3, 14.1 Hz,
1H), 1.95–1.85 (m, 2H), 1.80–1.61 (4H), 1.48 (m, 1H), 0.99 (s, 9H),
0.19 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=158.6, 153.5, 135.0,
134.4, 129.2, 127.7, 119.8, 113.7, 71.8, 71.3, 55.2, 35.2, 31.4, 30.2, 29.9, 25.7,
19.1, 18.2, ꢀ4.4 ppm; MS (ESI): m/z (%): 221 (100), 427 (10); HRMS
(ESI): m/z: calcd for C26H39O3Si+: 427.2668 [M+H]+; found: 427.2638;
elemental analysis calcd (%) for C26H38O3Si: C 73.2, H 9.0; found: C
73.3, H 9.1.
Acknowledgements
This work was generously supported by the Deutsche Forschungsgemein-
schaft.
[1] O. R. Gottlieb, K. Kubitzki, Naturwissenschaften 1983, 70, 119–126.
[2] L. Jurd, R. Y. Wong, Aust. J. Chem. 1984, 37, 1127–1133.
[3] I. L. DeAlbuquerque, C. Galeffi, C. G. Casinovi, G. B. Marini-Betto-
lo, Gazz. Chim. Ital. 1964, 94, 287–295.
[4] L. V. Alegrio, R. Braz-Filho, O. R. Gottlieb, Phytochemistry 1989,
28, 2359–2362.
[5] G. M. Keserꢁ, M. Nogradi, Stud. Nat. Prod. Chem. 1995, 17, 357–
394.
[6] S. Kadota, Y. Tezuka, J. K. Prasain, M. S. Ali, A. H. Banskota, Curr.
Top. Med. Chem. 2003, 3, 203–225.
ACHTUNGTRENNUNG(2S,6S)-2-[(4-tert-Butyldimethylsilyloxy)phenethyl]-6-[4-(methoxy)-
phenyl]-3,6-tetrahydro-2H-pyran (3S,7S)-10): The title compound was ob-
tained from (3R,7S)-9 (220 mg, 0.5 mmol) by following the procedure de-
scribed for (3R,7R)-10. Yield: 200 mg (90%); [a]2D0 =ꢀ8.2 (c=0.6 in
CH2Cl2); other analytical data are identical to those observed for
(3R,7R)-10.
[7] J. Yin, K. Kouda, Y. Tezuka, Q. Le Tran, T. Miyahara, Y. Chen, S.
Kadota, Planta Med. 2004, 70, 54–58.
[8] M. A. Sanz, T. Voigt, H. Waldmann, Adv. Synth. Catal. 2006, 348,
1511–1515.
(+)-epi-Centrolobine (3R,7R)-1: Tetrabutylammonium fluoride (73 mg,
0.2 mmol) was added to a solution of (3R,7R)-10 (100 mg, 0.2 mmol) in
dry THF at 08C. After complete conversion (TLC), the mixture was di-
luted with MTBE and washed with brine. The organic extracts were
dried with MgSO4, filtered, and evaporated. The residue was purified by
chromatography to give (+)-epi-centrolobine (3R,7R)-1 (70 mg, 98%).
[a]2D0 =+3.3 (c=0.5 in CH2Cl2); IR: n˜ =3309 (w), 2934 (m), 2860 (w),
1611 (m), 1511 (s), 1441 (m), 1243 (s), 1074 (s), 1031 cmꢀ1 (s); 1H NMR
(300 MHz, CDCl3): d=7.34 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.5 Hz, 2H),
6.91 (d, J=8.8 Hz, 2H), 6.72 (d, J=8.5 Hz, 2H), 5.61 (s, 1H), 4.84 (t, J=
5.3 Hz, 1H), 3.82 (s, 3H), 3.78 (m, 1H), 2.75 (ddd, J=5.1, 10.3, 14.1 Hz,
1H), 2.56 (ddd, J=6.4, 10.2, 13.9 Hz, 1H), 2.10 (dddd, J=5.3, 9.0, 10.0,
14.0 Hz, 1H), 1.98–1.88 (m, 2H), 1.81–1.61 (4H), 1.46 ppm (m, 1H);
13C NMR (75 MHz, CDCl3): d=158.6, 153.7, 134.2, 134.1, 129.4, 127.8,
115.1, 113.7, 71.9, 71.4, 55.2, 35.2, 31.2, 30.0, 29.9, 19.0 ppm; MS (ESI):
m/z: (%): 219 (50), 294 (50), 313 (100); HRMS (ESI): m/z: calcd for
C20H25O3+: 313.1804 [M+H]+; found: 313.1781; elemental analysis calcd
(%) for C20H24O3: C 76.9, H 7.7; found: C 76.6, H 7.9.
[9] S. Broussy, H. Waldmann, J. Comb. Chem. 2007, 9, 1138–1143.
[10] F. Colobert, R. Des Mazery, G. Solladie, M. C. Carreno, Org. Lett.
2002, 4, 1723–1725.
[11] P. A. Clarke, S. Santos, Eur. J. Org. Chem. 2006, 2045–2053.
[12] T. Washio, R. Yamaguchi, T. Abe, H. Nambu, M. Anada, S. Hashi-
moto, Tetrahedron 2007, 63, 12037–12046.
[13] P. A. Evans, J. Cui, S. J. Gharpure, Org. Lett. 2003, 5, 3883–3885.
[14] L. Boulard, S. BouzBouz, J. Cossy, X. Franck, B. Figadꢄre, Tetrahe-
dron Lett. 2004, 45, 6603–6605.
[15] K.-P. Chan, T.-P. Loh, Org. Lett. 2005, 7, 4491–4494.
[16] S. Marumoto, J. J. Jaber, J. P. Vitale, S. D. Rychnovsky, Org. Lett.
2002, 4, 3919–3922.
[17] V. Bçhrsch, J. Neidhçfer, S. Blechert, Angew. Chem. 2006, 118,
1324–1327; Angew. Chem. Int. Ed. 2006, 45, 1302–1305.
[18] V. Bçhrsch, S. Blechert, Chem. Commun. 2006, 1968–1970.
[19] G. B. Jones, S. B. Heaton, Tetrahedron: Asymmetry 1993, 4, 261–
272.
[20] K. Kubota, J. L. Leighton, Angew. Chem. 2003, 115, 976–978;
Angew. Chem. Int. Ed. 2003, 42, 946–948.
[21] J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512–519.
[22] A. E. Sutton, B. A. Seigal, D. F. Finnegan, M. L. Snapper, J. Am.
Chem. Soc. 2002, 124, 13390–13391.
[23] B. Schmidt, Eur. J. Org. Chem. 2003, 816–819.
[24] B. Schmidt, Chem. Commun. 2004, 742–743.
[25] B. Schmidt, J. Org. Chem. 2004, 69, 7672–7687.
[26] A. Roglans, A. Pla-Quintana, M. Moreno-MaÇas, Chem. Rev. 2006,
106, 4622–4643.
[27] B. Schmidt, Chem. Commun. 2003, 1656–1657.
[28] A. Roe, Org. React. 1949, 5, 193–226.
[29] A. H. L. Machado, M. A. de Sousa, D. C. S. Patto, L. F. S. Azevedo,
F. I. Bombonato, C. R. D. Correia, Tetrahedron Lett. 2009, 50, 1222–
1225.
(ꢀ)-epi-Centrolobine ((3S,7S)-1): The title compound was obtained from
(3S7S)-10 (50 mg, 0.1 mmol) by following the procedure described for
(+)-epi-centrolobine. Yield: 30 mg (80%); [a]2D0 =ꢀ3.6 (c=0.6 in
CH2Cl2); other analytical data are identical to those observed for (+)-
epi-centrolobine.
(ꢀ)-Centrolobine ((3R,7S)-1): HCl (aq, 4n, 130 mL, 0.26 mmol) was
added to a suspension of (3R,7R)-10 (110 mg, 0.3 mmol) in methanol
(2.5 mL). The mixture was stirred at ambient temperature for 12 h, and
then diluted with MTBE (10 mL). The organic layer was washed with
water (10 mL), and the aqueous layer was re-extracted with MTBE
(10 mL). The combined organic extracts were dried with MgSO4, filtered,
and the solvent was evaporated. The residue was purified by chromatog-
raphy to give (ꢀ)-centrolobine (75 mg, 92%). [a]2D0 =ꢀ83.2 (c=0.4 in
CH2Cl2); IR: n˜ =3365 (w), 2933 (m), 2837 (w), 1612 (m), 1512 (s), 1440
(m), 1244 (s), 1073 (s), 1033 cmꢀ1 (s); 1H NMR (300 MHz, CDCl3): d=
7.33 (d, J=8.5, 2H), 7.04 (d, J=8.5, 2H), 6.90 (d, J=8.8, 2H), 6.71 (d,
[30] B. Schmidt, R. Berger, unpublished results.
[31] K. Suzuki, Pure Appl. Chem. 1994, 66, 2175–2178.
11952
www.chemeurj.org
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11948 – 11953

Stereodivergent Synthesis of All Stereoisomers of Centrolobine
FULL PAPER
[32] P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2003.
[33] (ꢀ)-epi-Centrolobine was synthesized from d-glucose while this
work was in progress: C. R. Reddy, P. P. Madhavi, S. Chandrasekhar,
Synthesis 2008, 2939–2942.
[34] P. Schwab, R. H. Grubbs, J. W. Ziller, J. Am. Chem. Soc. 1996, 118,
100–110.
Received: July 23, 2009
Published online: September 29, 2009
Chem. Eur. J. 2009, 15, 11948 – 11953
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11953