Pd-catalyzed arylation reactions with phenol diazonium salts: Application in the synthesis of diarylheptanoids

Article abstract of DOI:10.1021/jo2002787

The first total synthesis of the natural product (3S,7R)-5,6-dehydro-de-O- methyl centrolobine and various analogues is reported, using a highly regio- and diastereoselective Mizoroki-Heck reaction of phenol diazonium salts and enantiopure dihydropyrans. The assigned relative configuration was confirmed by single-crystal X-ray structure analysis, but a revision of the absolute configuration is proposed based on polarimetric measurement.

Full text of DOI:10.1021/jo2002787

ARTICLE
pubs.acs.org/joc
Pd-Catalyzed Arylation Reactions with Phenol Diazonium Salts:
Application in the Synthesis of Diarylheptanoids
Bernd Schmidt,*,† Frank H€olter,† Alexandra Kelling,‡ and Uwe Schilde‡
†Institut fuer Chemie (Organische Synthesechemie) and ‡Institut fuer Chemie (Anorganische Chemie), Universitaet Potsdam,
Karl-Liebknecht-Strasse 24-25, D-14476 Potsdam-Golm, Germany
S Supporting Information
b
ABSTRACT: The first total synthesis of the natural product (3S,7R)-5,6-
dehydro-de-O-methyl centrolobine and various analogues is reported,
using a highly regio- and diastereoselective MizorokiꢀHeck reaction of
phenol diazonium salts and enantiopure dihydropyrans. The assigned
relative configuration was confirmed by single-crystal X-ray structure
analysis, but a revision of the absolute configuration is proposed based
on polarimetric measurement.
Chart 1. Structures of Curcumin (1) and Pyran-Type
’ INTRODUCTION
Diarylheptanoids (2ꢀ4a)
Diarylheptanoids are natural products occurring in various
plants.1 They share an aliphatic C7 chain with aromatic substituents,
often phenols, at the termini, and are very often bacteriostatic2 or
nematocidal3 agents. Curcumin (1),4 isolated from the rhizomes of
Curcuma longa, is an example for an acyclic diarylheptanoid and was
the only known diarylheptanoid for many decades. The second
diarylheptanoid to be discovered was centrolobine (2),5 which
occurs in the heartwood of amazonian trees of Centrolobium sp. in
both enantiomeric forms.6,7 Since the discovery of centrolobine in
1964, numerous other diarylheptanoids, and in particular pyran-type
diarylheptanoids, were isolated from various plants (Chart 1).
A particularly rich source of diarylheptanoid natural products
is Alpinia blepharocalyx, which is used in traditional Chinese folk
medicine for the treatment of gastrointestinal disorders and was
thoroughly investigated by Kadota et al. over the past decade.8
For example, they isolated and characterized (3S,7S)-5,6-dehy-
dro-de-O-methyl centrolobine (3)9 and its 7R-epimer 4a10 from
this source, along with several dihydroxylated derivatives, dimers,
and chalcone conjugates, which comprise the pyran core of 3 or
4a (Chart 1).10 Many of these compounds possess antiprolifera-
tive activity against human HT-1080 fibrosarcoma and murine
colon 26-L5 carcinoma cells. For several structurally related
compounds, antibacterial activities and antileishmanial activities
were detected.6,11
has attracted considerably less attention,18,21 probably because trans-
centrolobines have not been isolated from natural sources.
We have recently devised a stereodivergent route to all
stereoisomers of centrolobine that relies on an intermolecular
MizorokiꢀHeck reaction of cyclic enol ethers and a 4-methox-
ybenzene diazonium salt.22 MizorokiꢀHeck reactions with arene
diazonium salts were first described by Matsuda et al.23 but have
remained largely unexplored for quite some time.24 Over the past
decade, contributions from several groups25ꢀ40 have triggered a
renaissance of Pd-catalyzed coupling reactions with diazonium salts.
Synthetic efforts in this field have mostly been directed at the
synthesis of (ꢀ)-centrolobine. Various methods such as hetero-
DielsꢀAlder reactions,12 cross metathesisꢀreductive etherifica-
tion sequences,13,14 diastereoselective ring rearrangement meta-
thesis,15 Prins cyclizations,16,17 and oxidative18,19 or acid-catalyzed20
intramolecular etherifications have been used as key steps. A
common feature of these methods is the high cis-selectivity, which
is required if centrolobine or other cis-configured pyran-type
diarylheptanoids are the targets. The synthesis of trans-epimers
Received: February 10, 2011
Published: March 24, 2011
r
2011 American Chemical Society
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Scheme 1. Synthetic Plan for Dehydro-de-O-methyl
centrolobines
Scheme 2. Syntheses of Dihydropyrans 5aꢀc
During our studies directed at the synthesis of pyran-type diaryl-
heptanoids, we required a method for the introduction of phenols to
access not only aryl methyl ethers such as centrolobine but also
demethylated diarylheptanoids. A solution for this problem is the
use of benzyl-protected arene diazonium salts, which we applied to
the synthesis of rac-de-O-methyl centrolobine.41 However, we
experienced considerable difficulties with the final debenzylation
step, which was often associated with a reductive cleavage of the
tetrahydropyran ring and could not be achieved without concomi-
tant hydrogenation of an endocyclic CꢀC double bond. For these
reasons, we considered unprotected phenol diazonium salts as
coupling reagents. We have recently discovered that these com-
pounds are highly reactive electrophiles in the MizorokiꢀHeck
reaction with electron-deficient alkenes, such as acrylates and acrylic
amides, with reactivities often exceeding those observed for their
O-alkylated counterparts.42
Scheme 3. Synthesis of 7c via Olefination and Ester
Reduction
In this contribution, we report the first stereoselective synthesis of
the natural product (3S,7R)-5,6-dehydro-de-O-methyl centrolobine
(4a) and several non-natural derivatives. A Pd-catalyzed Mizoroki
ꢀHeck reaction of cyclic enol ethers 5 and phenol diazonium salts 6
was envisaged as the key step (Scheme 1).
’ RESULTS AND DISCUSSION
Synthesis of Cyclic Enol Ethers 5. We synthesized three
dihydropyrans 5aꢀc from a common precursor 8 (Scheme 2).
Allyl ether 8 was obtained in enantiomerically pure form as
previously described by us,22 using a Leighton allylation43 of
TBS-protected aldehyde 7c and a Williamson etherification of
the resulting homoallylic alcohol. Dihydropyran 5a (X = H)22 is
available from 8 in one step using the tandem RCM isomeriza-
tion sequence developed by Snapper et al.44 and by us.45ꢀ47 For
the synthesis of diastereomers 5b and 5c, allyl ether 8 was
cyclized in a ring closing metathesis reaction in the absence of
isomerization-promoting additives. The resulting dihydropyran
9 was epoxidized with m-CPBA, giving two diastereomeric
dihydropyran oxides 10a and 10b in a 1:1 ratio. These diaster-
eomers are easily separable by chromatography and were then
individually treated with Li amides to promote a rearrangement
to allylic alcohols. This reaction has originally been investigated
by Rickborn et al.48ꢀ50 and was further investigated by us51,52
and others,53 extending the research to include the synthesis of
cyclic enol ethers from dihydrofuran and dihydropyran oxides.
We found that for the trans-isomer 10a a highly regioselective
rearrangement to 5b was achieved with LDA, whereas partial
deprotonation at the 4-position was observed upon treatment of
the cis-diastereomer 10b with this base, resulting in the formation
of an undesired regioisomer. This insufficiency could be cor-
rected by using the sterically more demanding base Li-2,2,6,
6-tetramethylpiperidide (LiTMP), which gave 5c as a single
regioisomer.
Alternative Syntheses of TBS-Protected Aldehyde 7c.
Aldehyde 7c (Scheme 2) was originally synthesized from cou-
maric acid in four steps, following a literature procedure.54 We
found, however, that an alternative synthesis starting from
4-hydroxybenzaldehyde (11) is more convenient. This synthesis
involves TBS protection of 11, HornerꢀWadsworthꢀEmmons
olefination of 12, hydrogenation of 13,55 and finally partial
reduction of the ester 14 with DIBAl-H54 to give 7c in four
steps and 70% overall yield (Scheme 3).
Although this synthesis works well and provides the required
aldehyde 7c in useful quantities, we thought that an alternative
synthesis which uses the same precursor for both aryl substitu-
ents in diarylheptanoids such as 3 or 4a might be overall more
economical. Such a synthesis would require a MizorokiꢀHeck
reaction of a phenol diazonium salt 6a (Scheme 1, R = H) and
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Scheme 4. MizorokiꢀHeck Reaction of Diazonium Salts 6
Scheme 5. Synthesis of Diarylheptanoids 4
and Allyl Alcohol (15)
allyl alcohol (15). MizorokiꢀHeck reactions of allylic alcohols
and iodoarenes were investigated by Jefferey using two different
catalyst systems:56 with NBu4Cl as an additive, aldehydes 7 are
the preferred products because the Pd hydride species resulting
from β-hydride elimination is stabilized by complexation of
chloride and may efficiently catalyze a subsequent double bond
migration. Conversely, the addition of Ag57 or Tl salts58 results in
the preferred formation of alcohols 16 because the concentration
of halide is lowered, which results in a destabilization of the Pd
hydride species and consequently in a suppression of subsequent
isomerization reactions. MizorokiꢀHeck reactions of primary or
secondary allylic alcohols and arene diazonium salts have also
been investigated and normally give aldehydes or ketones,
respectively, as the major products.23,36,37,59,60 In particular, for
simple allyl alcohol (15), however, the reaction suffers from low
yields and insufficient selectivities, and in those cases where
methanol was used as a solvent, partial or complete acetal
formation was observed.37,59 Encouraged by our good results
for MizorokiꢀHeck reactions of phenol diazonium salts and
electron-deficient alkenes, we investigated the challenging sub-
strate 15 using the previously established standard conditions. In
contrast to the majority of Pd-catalyzed coupling reactions
previously described in the literature, we found that for phenol
diazonium salts better results are obtained in the presence of a
base.42 This might be attributed to the formation of a quinone
diazide, which is presumably less sensitive to decomposition by
attack of the nucleophilic solvent methanol. Thus, by using
ligandless Pd(OAc)2 as a precatalyst, NaOAc as a base, and
methanol as a solvent, we obtained allylic alcohol 16a from 6a
and 15 in 72% yield, along with 11% of aldehyde 7a. Interestingly,
4-methoxybenzene diazonium salt 6b reacts analogously with 15
to give 16b, albeit in lower yield (Scheme 4). The reaction of 6b
and 15 had previously been investigated using a different
precatalyst and base-free conditions, which is most likely the
crucial difference. Under these conditions, a mixture of regioi-
someric acetals was obtained.37
the presence of 1 equiv of TBACl, whereas aldehyde 7a was
isolated under these conditions in good yield and high selectivity.
This example underlines once more the enhanced stability of
phenol diazonium salts compared to other arene diazonium salts
to nucleophiles. The required aldehyde 7c was obtained from 7a
by silylation in high yield (Scheme 4).
Synthesis of 4a and Non-natural Analogues. For the
synthesis of the natural product (3S,7R)-5,6-dehydro-de-O-
methyl centrolobine (4a) and its non-natural analogues 4cꢀe,
the TBS-protected dihydropyran 5a was reacted with phenol
diazonium salts 6a and 6cꢀe using Pd(OAc)2 as a precatalyst,
basic conditions, and acetonitrile as a solvent (Scheme 5).
The mono-TBS-protected diarylheptanoids 17a and 17cꢀe
were obtained in fair to excellent yields and diastereomeric ratios
exceeding 19:1, as determined by 1H NMR spectroscopy. Most
importantly, subsequent double bond migration, which is known
to be a problem in Pd-catalyzed arylations with iodoarenes,61 is
fully suppressed in these reactions. The synthesis of 4a and its
non-natural analogues 4cꢀe was completed by deprotection
with TBAF. All spectroscopical and physical data obtained for
synthetic 4a match those reported by Kadota et al. for the natural
product,10 except for the specific rotation. While these authors
reported a value of [R]24D = ꢀ12.3 (c 0.335, methanol), we found
not only a different value but also a different sign for the specific
rotation, that is, [R]24D = þ48.7 (c 0.37, methanol). We are confi-
dent that we actually synthesized (3S,7R)-configured 4a because the
assigned relative configuration was confirmed by single-crystal X-ray
structure analysis of our synthetic material,62 and the absolute con-
figuration at stereocenter C3 (diarylheptanoid numbering, refer to
Scheme 1) is a result of Leighton’s well-established allylation method,
using the (S,S)-configured reagent derived from cyclohexanedi-
amine.43 Furthermore, we previously used (S)-8 to synthesize
(ꢀ)-centrolobine, whose absolute configuration has been secured
by total synthesis,63 chiroptical methods,64 and very recently by crys-
tallographic methods.19 Nevertheless, we tried to unambigously
prove the assigned (3S,7R)-configuration of dextrorotatory trans-
de-O-methyl-5,6-dehydrocentrolobines 4 by X-ray crystallography
using anomalous scattering. The presence of heavy atoms is
required for this method, and the bromo-analogue 4e seemed to
For the selective synthesis of aldehyde 7a, tetrabutyl ammo-
nium chloride (TBACl) was added to the reaction mixture, and
the solvent methanol was replaced by acetonitrile. TBACl, to the
best of our knowledge, has not been successfully used as an
additive in Pd-catalyzed coupling reactions with arene diazonium
salts. Interestingly, the reaction of 15 and 6b failed completely in
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Scheme 6. Synthesis of a Bis-4-bromobenzoate Derivative 18
Scheme 8. Pd-Catalyzed Arylation of 5b and 5c
Scheme 7. Synthesis of a Non-natural Dihydropyran Oxide-
Type Diarylheptanoid 20
Scheme 9. Attempted Arylation of 5b
be a suitable derivative. Unfortunately, 4e was repeatedly isolated
as a viscous oil, and all attempts to obtain single crystals failed.
Therefore, 4a was converted into its bis-4-bromobenzoate 18,
which crystallized nicely. However, the crystals were of insufficient
quality for single-crystal structure analysis (Scheme 6).
We cannot conclusively decide whether the (3S,7R)-config-
uration assigned to the natural product is correct or not. However,
we are confident that (3S,7R)-4a is (þ)-4a, hence (ꢀ)-4a must be
(3R,7S)-4a. It should be noted that the originally assigned absolute
configuration of naturally occurring (ꢀ)-4a has recently been
challenged by Rogano and R€uedi, who also proposed a revision to
(3R,7S)-4a, based on chiroptical comparison.19
Apart from centrolobines (2 and ent-2) and 5,6-dehydrocen-
trolobines (3 or ent-3, 4a or ent-4a), several pyran-type diarylhepta-
noids bearing oxygen substituents in the 5- or 6-position were isolated
from various sources, including Alpinia blepharocalyx10 and Zingiber
officinale.65 We synthesized a non-natural 5,6-dioxygenated diarylhep-
tanoid 20 from 17a by epoxidation with m-CPBA and subsequent
desilylation. The phenol substituent at C7, which adopts predomi-
nantly a pseudoaxial orientation, efficiently directs the epoxidizing
agent to the opposite face of the CꢀC double bond, resulting in a
high trans-diastereoselectivity, while the sterically less demanding and
more remote alkyl chain at C3 seems to have considerably less
influence on the stereochemical outcome (Scheme 7).
C3 exerts a strong influence on the stereochemical course of the Pd-
catalyzed arylation, and we were therefore intrigued by the oppor-
tunity to test the effect of a second substituent in close proximity to
the reacting double bond. Using the conditions previously estab-
lished for the arylation with phenol diazonium salts, the cis-config-
ured dihydropyran 5c was reacted with 6a. This reaction yields
exclusively tetrahydropyranone trans-21 in good yield and high
diastereoselectivity. Deprotection with TBAF in THF proceeded
smoothly to trans-22 without noticeable epimerization (Scheme 8).
Our assignment of a trans-configuration is based on a compar-
ison with the spectroscopical data reported for a similar com-
pound, which was previously synthesized by Clarke and Martin
in the course of a synthesis of rac-centrolobine via a Maitland
ꢀJapp reaction. We observed for the signal of H7 a pseudotriplet
at δ = 5.18 ppm with a coupling constant of 5.4 Hz, which
matches the data reported by Clarke and Martin very well. These
authors also isolated and characterized a cis-epimer, for which H7
appears as a doublet of doublets with J(H6R-H7) of 10.7 Hz and
J(H6β-H7) of 3.8 Hz.66
The reaction of the trans-configured diastereomer 5b under
otherwise identical conditions resulted in a quantitative recovery
of the starting material. This failure can be understood by
assuming a dominant directing effect of the substituent at C3,
which directs the incoming σ-aryl-Pd complex to the opposite
face of the C6ꢀC7 double bond. Upon cis-insertion, however,
the catalytic cycle stops because no β-hydrogen in the required
syn-orientation is available and subsequent β-hydride elimination
is therefore inhibited (Scheme 9).
With a view toward the synthesis of pyran-type diarylhepta-
noids which are oxygenated at C5 but not at C6, we investigated the
MizorokiꢀHeck reactions of dihydropyrans 5b and 5c. It is evident
from the examples discussed above (Scheme 5) that a substituent at
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Scheme 10. Arylation of 5c
temperature and stirred for 6 h. It was then washed with a saturated
aqueous solution of Na2SO3 (20 mL), the organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (50 mL). The
combined organic layers were dried with MgSO4, filtered, and evapo-
rated. The resulting diastereomers were separated by column chroma-
tography on silica (eluent hexanes/MTBE 3:1) to give 10a (280 mg, 0.84
mmol, 35%) and 10b (290 mg, 0.87 mmol, 36%) as colorless liquids.
Analytical data for (4-(2-((1R,4S,6S)-3,7-dioxabicyclo[4.1.0]heptan-4-
yl)ethyl)phenoxy)-(tert-butyl)dimethylsilane (10a): [R]24 = þ13.4
D
1
(c 0.35, CH2Cl2); H NMR (300 MHz, CD3C(O)CD3) δ 7.06 (d, J =
8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 4.19 (dd, J = 13.5, 4.1 Hz, 1H), 3.75
(d, J = 13.5 Hz, 1H), 3.31ꢀ3.17 (3H), 2.66 (ddd, J = 13.8, 8.4, 5.4 Hz, 1H),
2.53 (ddd, J = 13.9, 8.3, 8.3 Hz, 1H), 1.97 (ddd, J = 14.5, 2.3, 2.3 Hz, 1H),
1.69ꢀ1.56 (3H), 0.98 (s, 9H), 0.18 (s, 6H); 13C NMR (75 MHz,
CD3C(O)CD3) δ 154.6 (0), 136.0 (0), 130.2 (1), 120.7 (1), 69.7 (1),
66.4 (2), 51.5 (1), 51.1 (1), 38.5 (2), 32.4 (2), 31.6 (2), 26.1 (3), 18.8
(0), ꢀ4.2 (3). Analytical data for (4-(2-((1S,4S,6R)-3,7-dioxabicyclo-
[4.1.0]heptan-4-yl)ethyl)phenoxy)-(tert-butyl)dimethylsilane (10b):
[R]24D = þ17.6 (c 0.34, CH2Cl2); 1H NMR (300 MHz, CD3C(O)CD3) δ
7.06 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 4.07 (d, J = 13.3 Hz, 1H),
3.76 (dd, J = 13.3, 0.5 Hz, 1H), 3.31 (dd, J = 5.7, 4.2 Hz, 1H), 3.10 (m, 1H),
2.96 (d, J = 4.1 Hz, 1H), 2.69ꢀ2.48 (2H), 1.91 (ddd, J = 15.1, 5.8, 3.9 Hz,
1H), 1.66ꢀ1.55 (3H), 0.97 (s, 9H), 0.18 (s, 6H); 13C NMR (75 MHz,
CD3C(O)CD3) δ 154.6 (0), 136.0 (0), 130.3 (1), 120.7 (1), 72.6 (1), 65.4
(2), 50.0 (1), 49.4 (1), 38.6 (2), 31.4 (2), 30.7 (2), 26.1 (3), 18.2 (0), ꢀ4.2
(3); IR (neat) ν 2931 (w), 2856 (w), 1608 (w), 1509 (s), 1252 (s); MS
(EI) m/z 334 ([M]þ, 15), 264 (37), 219 (100); HRMS (EI) calcd for
C19H30O3Si[M]þ 334.1964, found 334.1970. Anal. Calcd for C19H30O3Si:
C, 68.2; H, 9.0. Found: C, 67.9; H, 8.9.
In contrast to 5b, the cis-configured 5c reacts with the σ-aryl-
Pd complex to an insertion product with a favorable syn-orienta-
tion of Pd and β-hydrogen, and the catalytic cycle can proceed
with the β-hydride elimination to an enol, which tautomerizes to
the ketone trans-21 (Scheme 10).
’ CONCLUSIONS
In summary, we report the first total synthesis of the diaryl-
heptanoid trans-(þ)-5,6-dehydro-de-O-methyl centrolobine,
using a Pd-catalyzed coupling of a phenol diazonium salt as the
key step. Our results suggest that the original assignment of the
(3S,7R)-configuration to the naturally occurring laevorotatory
compound should be revised to (3R,7S). Future work in this area
will show whether or not this revision has implications on the
assigned absolute configurations of other trans-configured pyran-
type diarylheptanoids. From a methodology point of view, we
could demonstrate that phenol diazonium salts are interesting
and versatile reagents for Pd-catalyzed CꢀC bond-forming
reactions. They are not only highly reactive arylating agents
but also enable a considerable reduction of protecting group
effort in target molecule synthesis.
(2S,4S)-2-(4-(tert-Butyldimethylsilyloxy)phenethyl)-3,4-
dihydro-2H-pyran-4-ol (5b). To a solution of diisopropylamine
(0.20 mL, 1.5 mmol) in THF (5.0 mL) was added BuLi (2.5 M solution in
hexanes, 0.8 mL, 2.0 mmol) at 0 °C. The solution was stirred at this
temperature for 1 h, and then a solution of 10a (330 mg, 1.0 mmol) in THF
(5.0 mL) was added dropwise at this temperature. Stirring was continued
for 5 h, and a saturated solution of NH4Cl (20 mL) was added. The organic
layer was separated, and the aqueous layer was extracted with MTBE
(150 mL). The combined organic extracts were dried with MgSO4, filtered,
and evaporated. The residue was purified by chromatography on silica
(eluent hexanes/MTBE 1:1) to give 5b (170 mg, 0.51 mmol, 51%) as
a colorless liquid: [R]24 = ꢀ84.9 (c 0.79, CH2Cl2); 1H NMR
D
(300 MHz, C6D6) δ 6.98 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H),
6.39 (d, J = 6.1 Hz, 1H), 4.70 (m, 1H), 3.89ꢀ3.79 (2H), 2.75 (ddd, J = 13.9,
10.3, 5.4 Hz, 1H), 2.58 (ddd, J= 13.9, 10.0, 6.5 Hz, 1H), 1.81 (dddd, J= 13.7,
8.4, 8.4, 5.5 Hz, 1H), 1.68ꢀ1.54 (2H), 1.34 (ddd, J= 13.9, 12.2, 3.9 Hz, 1H),
1.01 (s, 9H), 0.13 (s, 6H); 13C NMR (75 MHz, C6D6) δ 154.6 (0), 147.3
(1), 135.4 (0), 130.1 (1), 120.7 (1), 103.8 (1), 71.0 (1), 60.1 (1), 37.9 (2),
37.7 (2), 31.5 (2), 26.3 (3), 18.8 (0), ꢀ4.0 (3); IR (neat) ν 3345 (w),
2928 (m), 2858 (m), 1639 (m), 1509 (s), 1241 (s); MS (EI) m/z 334
([M]þ, 52), 221 (60), 181 (100); HRMS (EI) calcd for C19H30O3Si[M]þ
334.1959, found 334.1950. Anal. Calcd for C19H30O3Si: C, 68.2; H, 9.0.
Found: C, 68.0; H, 8.9.
’ EXPERIMENTAL SECTION
(S)-tert-Butyl(4-(2-(3,6-dihydro-2H-pyran-2-yl)ethyl)phen-
oxy)dimethylsilane (9). To a solution of 8 (1.00 g, 2.9 mmol) in
toluene (10 mL) was added first generation Grubbs’ catalyst A (60 mg,
2.5 mol %). The solution was heated to 80 °C for 2 h, cooled to ambient
temperature, and all volatiles were evaporated. The residue was purified by
chromatography on silica (eluent hexanes/MTBE 10:1) to give 9 (0.80 g,
2.5 mmol, 86%) as a colorless liquid: [R]24D = þ20.7 (c 0.5, CH2Cl2); 1H
NMR (300 MHz, CDCl3) δ 7.05 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.6 Hz,
2H), 5.80 (ddd, J = 10.7, 4.4, 2.2 Hz, 1H), 5.72 (dm, J = 10.2 Hz, 1H),
4.22ꢀ4.15 (2H), 3.46 (ddd, J = 13.3, 8.8, 4.4 Hz, 1H), 2.74 (ddd, J = 14.0,
9.4, 5.5 Hz, 1H), 2.63 (ddd, J = 13.8, 9.1, 7.2 Hz, 1H), 2.06ꢀ1.95 (2H),
1.94ꢀ1.65 (2H), 0.98 (s, 9H), 0.19 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 153.6 (0), 134.8 (0), 129.3 (1), 126.4 (1), 124.3 (1), 119.8 (1), 72.7 (1),
65.9 (2), 37.7 (2), 31.1 (2), 30.9 (2), 25.7 (3), 18.2 (0), ꢀ4.4 (3); IR (neat)
ν 2928 (w), 1508 (s), 1250 (s), 1091 (m); MS (ESI) m/z 319 ([M þ
H]þ,100), 297 (100), 281 (20), 221 (50); HRMS (ESI) m/z calcd for
C19H31O2Si[MþH]þ 319.2093, found 319.2101.
(2S,4R)-2-(4-(tert-Butyldimethylsilyloxy)phenethyl)-3,4-
dihydro-2H-pyran-4-ol (5c). To a solution of 2,2,6,6-tetramethylpi-
peridine (0.30 mL, 1.8 mmol) in THF (10 mL) was added a solution of BuLi
(2.5Msolutioninhexanes, 0.60mL, 1.5mmol) atꢀ40 °C. The solution was
stirred for 1 h, and then a solution of 10b (340 mg, 1.0 mmol) in THF
(10 mL) was added dropwise at ꢀ40 °C. Stirring was continued for 2 h, and
the reaction was quenched by addition of a saturaed aqueous solution of
NH4Cl-L€osung (20 mL). The organic layer was separated, and the aqueous
layer was extracted with MTBE (150 mL). The combined organic extracts
were dried with MgSO4, filtered, and evaporated. The residue was purified by
chromatography on silica (eluent hexanes/MTBE 1:1) to give 5c (200 mg,
Synthesis of Dihydropyran Oxides 10a,b. To a solution of 9
(0.75 g, 2.4 mmol) in CH2Cl2 (50 mL) was added m-CPBA (0.60 g, 2.4
mmol) at 0 °C. The resulting suspension was warmed to ambient
0.60 mmol, 60%) as a colorless liquid: [R]24 = ꢀ9.4 (c 0.33, CH2Cl2);
D
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ARTICLE
1H NMR (300 MHz, C6D6) δ 6.98 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz,
2H), 6.28 (dd, J = 6.2, 1.0 Hz, 1H), 4.59 (dt, J = 6.2, 1.9 Hz, 1H), 4.09
(m, 1H), 3.64 (dddd, J = 13.0, 10.9, 4.3, 2.0 Hz, 1H), 2.67 (ddd, J = 13.8, 9.4,
6.5 Hz, 1H), 2.55 (ddd, J = 13.8, 9.5, 6.9 Hz, 1H), 1.82 (dddd, J = 13.9, 8.6,
8.6, 5.4 Hz, 1H), 1.68 (ddt, J= 12.9, 6.5, 1.7 Hz, 1H), 1.54 (dddd, J= 14.0, 9.9,
6.9, 4.3 Hz, 1H), 1.40 (ddd, J = 13.0, 11.3, 9.2 Hz, 1H), 1.01 (s, 9H), 0.13
(s, 6H);13CNMR(75 MHz, C6D6) δ154.6 (0), 145.2 (1), 135.3 (0), 130.1
(1), 120.7 (1), 106.6 (1), 74.4 (1), 63.4 (1), 38.8 (2), 37.8 (2), 31.3 (2), 26.3
(3),18.8(0),ꢀ4.0 (3); IR (neat) ν2928 (w), 2857 (w), 1640 (w), 1509 (s),
1251 (s); MS (EI) m/z 334 ([M]þ, 10), 264 (20), 221 (100); HRMS (EI)
calcd for C19H30O3Si[M]þ 334.1964, found 334.1976. Anal. Calcd for
C19H30O3Si: C, 68.2; H, 9.0. Found: C, 67.6; H, 8.8.
4-(tert-Butyldimethylsilyloxy)benzaldehyde (12) (ref 55).
To a solution of 4-hydroxybenzaldehyde (11, 4.00 g, 33.0 mmol) in
CH2Cl2 (25 mL) was added imidazole (4.50 g, 66.0 mmol) at 0 °C,
followed after 15 min by TBSCl (5.00 g, 33.0 mmol). The mixture was
stirred for 12 h at ambient temperature, diluted with MTBE (10 mL),
and washed with brine (25 mL). The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (50 mL). The combined
organic extracts were dried with MgSO4, filtered, and evaporated. The
residue was purified by chromatography on silica (eluent cyclohexane/
MTBE 10:1) to give 12 (6.40 g, 27.0 mmol, 82%) as a colorless liquid:
1H NMR (300 MHz, CDCl3) δ 9.88 (s, 1H), 7.78 (d, J = 8.7 Hz, 2H),
6.94 (d, J = 8.5 Hz, 2H), 0.99 (s, 9H), 0.25 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 190.9 (1), 161.5 (0), 131.9 (1), 130.4 (1), 120.5 (0), 25.5 (3),
18.2 (0), ꢀ4.4 (3).
organic layers were dried with MgSO4, filtered, and evaporated. The
residue was purified by chromatography on silica (eluent hexanes/
MTBE 5:1) to give 7c (2.50 g, 9.5 mmol, 98%) as a colorless liquid.
Alternatively, the title compound was synthesized from 7a: To a solution
of 7a (0.64 g, 4.3 mmol) in CH2Cl2 (10 mL) was added imidazole (0.32
g, 4.7 mmol) at 0 °C. The mixture was stirred for 15 min, and TBSCl
(0.71 g, 4.7 mmol) was added. It was allowed to warm to ambient
temperature, and stirring was continued for 12 h. The resulting suspen-
sion was diluted with MTBE (25 mL) and washed with brine (10 mL).
The organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (40 mL). The combined organic extracts were dried with
MgSO4, filtered, and evaporated. The residue was purified by chroma-
tography on silica (eluent cyclohexane/MTBE 5:1) to give 7c (1.05 g,
4.0 mmol, 92%) as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ
9.81 (t, J = 1.5 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H),
2.92ꢀ2.87 (2H), 2.78ꢀ2.70 (2H), 0.98 (s, 9H), 0.19 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 201.8 (0), 154.0 (0), 132.9 (0), 129.1 (1), 120.1
(1), 45.5 (2), 27.3 (2), 25.7 (3), 18.2 (0), ꢀ4.5 (3); IR (neat) ν 2955
(w), 2929 (w), 2857(w), 1724 (m), 1509 (s), 1251 (s), 911 (s); MS
(ESI) m/z 265 ([M þ H]þ, 20), 221 (100); HRMS (ESI) m/z calcd for
C15H25O2Si[MþH]þ 265.1624, found 265.1646. Anal. Calcd for
C15H24O2Si: C, 68.1; H, 9.2. Found: C, 67.9; H, 9.4.
3-(4-Hydroxyphenyl)propanal (7a) (ref 67). To a suspension
of 6a (208 mg, 1.0 mmol), allyl alcohol (15, 140 μL, 2.0 mmol), NaOAc
(246 mg, 3.0 mmol), and TBACl (278 mg, 1.0 mmol) in CH3CN
(5.0 mL) was added Pd(OAc)2 (5.6 mg, 2.5 mol %) at 0 °C. The mixture
was stirred for 6 h at this temperature, all volatiles were evaporated, and
the residue was chromatographed on silica (eluent hexanes/MTBE 2:1)
to give 7a (104 mg; 0.7 mmol, 69%) as a colorless liquid: 1H NMR (300
MHz, CDCl3) δ 9.81 (t, J = 1.4 Hz, 1H), 7.06 (d, J = 8.5 Hz, 2H), 6.76
(d, J = 8.5 Hz, 2H), 4.85 (s, 1H), 2.93ꢀ2.85 (2H), 2.78ꢀ2.70 (2H); 13C
NMR (75 MHz, CDCl3) δ 202.7 (1), 154.1 (0), 132.1 (0) 129.3 (1),
115.4 (1), 45.4 (2), 27.2 (2); IR (neat) ν 3368 (m), 1708 (s), 1612 (m),
1514 (s), 1444 (m), 1218 (s); MS (ESI) m/z 151 ([M þ H]þ, 34), 133
(100); HRMS (ESI) calcd for C9H11O2[M þ H]þ 151.0759, found
151.0758. Anal. Calcd for C9H10O2: C, 72.0; H, 6.7. Found: C, 71.7;
H, 6.7.
(E)-Ethyl-3-(4-(tert-butyldimethylsilyloxy)phenyl)acrylate
(13) (ref 55). To a solution of triethylphosphonoacetate (5.7 mL, 29.0
mmol) in THF (50 mL) was added NaH (60% dispersion in mineral oil,
1.10 g, 29.0 mmol) at 0 °C. Stirring was continued for 15 min, and 12
(6.20 g, 26.0 mmol) was added. The resulting suspension was stirred for
12 h and washed with water (25 mL) and then with a saturated aqueous
solution of NaHCO3 (25 mL). The organic layer was separated, and the
aqueous layer was extracted with MTBE (150 mL). The combined
organic layers were dried with MgSO4, filtered, and evaporated. The
residue was purified by chromatography on silica (eluent cyclohexane/
MTBE 10:1) to give 13 (7.10 g, 23.0 mmol, 89%): 1H NMR (300 MHz,
CDCl3) δ 7.63 (d, J = 16.0 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 6.83 (d, J =
8.6 Hz, 2H), 6.30 (d, J = 16.0 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.33
(t, J = 7.1 Hz, 3H), 0.98 (s, 9H), 0.22 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 167.3 (0), 157.8 (0), 144.3 (0), 129.6 (1), 127.8 (1), 120.5
(1), 115.9 (1), 60.3 (2), 25.6 (3), 18.2 (0), 14.4 (3), ꢀ4.4 (3).
Ethyl-3-(4-(tert-butyldimethylsilyloxy)phenyl)propanoate
(14) (ref 55). To a solution of 13 (7.10 g, 23.0 mmol) in ethanol
(50 mL) was added Pd(OH)2/C (10 wt %, 71 mg). The solution was
saturated with hydrogen and stirred under an atmosphere of hydrogen
(1 bar) for 12 h at ambient temperature. The suspension was filtered
through Celite, and all volatiles were removed in vacuo. The residue was
purified by chromatography on silica (eluent cyclohexane/MTBE 5:1) to
give 14 (7.00 g, 23.0 mmol, 99%) as a colorless liquid: 1H NMR (300
MHz, CDCl3) δ 7.04 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 7.1 Hz, 2H), 4.12
(q, J = 7.1 Hz, 2H), 2.88 (t, J = 7.8 Hz, 2H), 2.57 (t, J = 7.7 Hz, 2H), 1.23
(t, J = 7.1 Hz, 3H), 0.97 (s, 9H), 0.18 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 173.0 (0), 154.0 (0), 133.2 (0), 129.1 (1), 120.0 (1), 60.3 (2),
36.2 (2), 30.2 (2), 25.7 (3), 18.2 (0), 14.2 (3), ꢀ4.5 (3); MS (ESI) m/z
309 ([M þ H]þ, 55), 263 (50), 221 (100); HRMS (ESI) m/z calcd for
C17H29O3Si[M þ H]þ 309.1886, found 309.1859.
(E)-4-(3-Hydroxyprop-1-enyl)phenol (16a) (ref 68). To a
suspension of 6a (208 mg, 1.0 mmol), allyl alcohol (15, 140 μL, 2.0
mmol), and NaOAc (246 mg, 3.0 mmol) in methanol (5.0 mL) was
added Pd(OAc)2 (5.6 mg, 2.5 mol %) at 0 °C. The reaction mixture was
stirred at this temperature for 6 h and then evaporated. The residue was
purified by chromatography on silica (eluent hexanes/MTBE 1:1) to
give 16a (108 mg, 0.72 mmol, 72%) as a colorless solid: mp
1
117ꢀ119 °C; H NMR (300 MHz, CD3OD) δ 7.23 (d, J = 8.5 Hz,
2H), 6.73 (d, J = 8.6 Hz, 2H), 6.50 (d, J = 15.9 Hz, 1H), 6.16 (dt, J = 15.8,
5.9 Hz, 1H), 4.18 (dd, J = 5.9, 1.4 Hz, 2H); 13C NMR (75 MHz,
CD3OD) δ 158.3, 132.0, 130.1, 128.8, 126.8, 116.4, 64.1; IR (neat) ν
3295 (w), 1605 (m), 1509 (s), 1246 (s); MS (ESI) m/z 151 ([M þ H]þ,
100), 133 (60); HRMS (ESI) calcd for C9H11O2[M þ H]þ 151.0759,
found 151.0745. Anal. Calcd for C9H10O2: C, 72.0; H, 6.7. Found: C,
71.5; H, 6.7.
(E)-3-(4-Methoxyphenyl)prop-2-en-1-ol (16b) (ref 69). To a
suspension of 6b (222 mg, 1.0 mmol), allyl alcohol (15, 140 μL, 2.0
mmol), and NaOAc (246 mg, 3.0 mmol) in methanol (5.0 mL) was
added Pd(OAc)2 (5.6 mg, 2.5 mol %) at 0 °C. The reaction mixture was
stirred at this temperature for 6 h, evaporated, and the residue was
purified by chromatography on silica (eluent hexanes/MTBE 5:1) to
give 16b (90 mg, 0.55 mmol, 55%) as a colorless solid: mp 78ꢀ80 °C;
1H NMR (300 MHz, CDCl3) δ 7.32 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.8
Hz, 2H), 6.55 (d, J = 15.9 Hz, 1H), 6.23 (dt, J = 15.9, 5.9 Hz, 1H), 4.29 (t,
J = 4.5 Hz, 2H), 3.81 (s, 3H), 1.58 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3) δ 159.3 (0), 130.9 (1), 129.4 (0), 127.6 (1), 126.3 (1), 114.0 (1),
63.9 (2), 55.3 (3); IR (neat) ν 3359 (w), 2841 (w), 1605 (m), 1512 (m),
3-(4-(tert-Butyldimethylsilyloxy)phenyl)propanal (7c) (ref
54). To a solution of 14 (3.00 g, 9.7 mmol) in CH2Cl2 (50 mL) was
slowly added DIBAl-H (1.1 M solution in cyclohexane, 10.5 mL, 11.6
mmol) at 78 °C. The reaction was quenched after 2 h by addition of
methanol (20 mL) and warmed to ambient temperature. HCl (aqueous,
1 M, 20 mL) was added, and the organic layer was separated. The
aqueous layer was extracted with CH2Cl2 (100 mL), and the combined
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ARTICLE
1245 (s); MS (ESI) m/z 165 ([M þ H]þ, 12), 147 (100); HRMS (ESI)
calcd for C10H13O2[M þ H]þ 165.0916, found 165.0911. Anal. Calcd
for C10H12O2: C, 73.2; H, 7.4. Found: C, 72.9; H, 7.3.
2-Bromo-4-((2S,6R)-6-(4-(tert-butyldimethylsilyloxy)phe-
nethyl)-5,6-dihydro-2H-pyran-2-yl)-phenol (17e). As described
above for 17a, the title compound was obtained from 5a (640 mg, 2.0
mmol) and 6e (690 mg, 2.4 mmol) as a colorless liquid: yield 550 mg
(56%); [R]24D = þ51.4 (c 0.5, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ
7.49 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 6.4, 2.0 Hz, 1H), 7.02 (d, J = 8.3 Hz,
1H), 6.77 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 8.5 Hz, 2H), 6.05 (ddd, J = 10.1,
4.6, 2.2 Hz, 1H), 5.92 (dm, J = 10.1 Hz, 1H), 5.54 (br s, 1H), 5.19 (br s,
1H), 3.44 (dddd, J = 8.6, 8.6, 4.0, 4.0 Hz, 1H), 2.63 (ddd, J = 13.9, 8.8, 5.2
Hz, 1H), 2.42 (ddd, J = 13.8, 8.2, 8.2 Hz, 1H), 2.10ꢀ1.94 (2H), 1.81
(dddd, J = 13.8, 8.6, 8.6, 5.2 Hz, 1H), 1.64 (dddd, J = 12.5, 8.5, 8.5, 3.9 Hz,
1H), 0.97 (s, 9H), 0.17 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 153.5 (0),
151.8 (0), 135.11 (0), 134.6 (0), 131.9 (1), 129.5 (1), 129.2 (1), 126.9
(1), 126.6(1), 119.7(1), 115.8(1), 110.0 (0), 73.1(1), 66.2 (1), 37.4 (2),
31.0 (2), 30.6 (2), 25.7 (3), 18.2 (0), ꢀ4.4 (3); IR (neat) ν 3263 (w),
2928 (m), 1606 (m), 1508 (s), 1251 (s), 1169 (m), 1059 (m); MS (ESI)
m/z 491 (75), 489 ([M þ H]þ, 80), 471 (100), 221 (30); HRMS (ESI)
calcd for C25H34BrO3Si[M þ H]þ 489.1415, found 489.1461. Anal.
Calcd for C25H33BrO3Si: C, 61.3; H, 6.8. Found: C, 61.2; H, 6.8.
4-((2S,6R)-6-(4-(tert-Butyldimethylsilyloxy)phenethyl)-5,6-
dihydro-2H-pyran-2-yl)phenol (17a). To a solution of 5a (100 mg,
0.31 mmol), 6a (65 mg, 0.31 mmol), and NaOAc (76 mg, 0.93 mmol) in
acetonitrile (5.0 mL) was added Pd(OAc)2 (0.8 mg, 2.5 mol %). The
mixture was stirred at ambient temperature until the evolution of gas had
ceased (approximately 3 h), evaporated, and the residue was suspended in
MTBE (10 mL). This suspension was filtered through Celite, all volatiles
were removed in vacuo, and the residue was purified by chromatography on
silica (eluent hexanes/MTBE 5:1) to give 17a (120 mg, 0.29 mmol, 94%) as
a colorless solid: mp 121ꢀ123 °C; [R]24D = þ46.1 (c 1.05, CH2Cl2); 1H
NMR (300 MHz, CDCl3) δ 7.29 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.6 Hz,
2H), 6.75 (d, J = 8.5 Hz, 2H), 6.62 (d, J = 8.5 Hz, 2H), 6.03 (ddd, J = 10.3,
4.4, 2.2 Hz, 1H), 5.95 (m, 1H), 5.23 (br s, 1H), 5.01 (s, 1H), 3.48 (dddd, J=
4.0, 4.0, 8.6, 8.6 Hz, 1H), 2.62 (ddd, J = 13.8, 8.8, 5.1 Hz, 1H), 2.41 (ddd, J =
13.8, 8.2, 8.2 Hz, 1H), 2.02 (m, 2H), 1.82 (dddd, J = 13.8, 8.7, 8.6, 5.1 Hz,
1H), 1.62 (dddd, J = 12.5, 8.5, 8.5, 3.8 Hz, 1H), 0.97 (s, 9H), 0.17 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 155.2 (0), 153.4 (0), 134.7 (0), 133.4 (0),
130.0 (1), 129.3 (1), 127.5 (1), 126.0 (1), 119.7 (1), 115.0 (1), 73.7 (1),
66.0 (1), 37.5 (2), 31.1 (2), 30.7 (2), 25.7 (3), 18.2 (0), ꢀ4.4 (3); IR (neat)
ν 3267 (w), 2927 (w), 2856 (w), 1508 (s), 1250 (s), 1168 (m); MS (ESI)
m/z 411 ([M þ H]þ, 100), 393 (75), 221 (25); HRMS (ESI) calcd for
C25H35O3Si[M þ H]þ 411.2355, found 411.2200. Anal. Calcd for
C25H34O3Si: C, 73.1; H, 8.4. Found: C, 73.1; H, 8.5.
Methyl-5-((2S,6R)-6-(4-(tert-butyldimethylsilyloxy)phen-
ethyl)-5,6-dihydro-2H-pyran-2-yl)-2-hydroxybenzoate (17c).
As described above for 17a, the title compound was obtained from 5a
(318 mg, 1.0 mmol) and 6c (266 mg, 1.0 mmol) as a colorless liquid: yield
444 mg (95%); [R]24D = þ60.3 (c 0.50, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 10.81 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 8.6, 2.3 Hz,
1H), 7.01 (d, J = 8.6 Hz, 1H), 6.75 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.5 Hz,
2H), 6.07 (ddd, J = 10.3, 4.6, 2.2 Hz, 1H), 5.95 (dm, J = 10.2 Hz, 1H), 5.21
(br s, 1H), 3.95 (s, 3H), 3.43 (dddd, J = 8.6, 8.6, 4.0, 4.0 Hz, 1H), 2.64
(ddd, J = 13.8, 9.0, 4.7 Hz, 1H), 2.40 (ddd, J = 13.9, 8.2, 8.2 Hz, 1H),
2.09ꢀ1.98 (2H), 1.81 (dddd, J = 13.8, 8.7, 8.7, 5.1 Hz, 1H), 1.63 (dddd,
J = 11.7, 8.1, 8.1, 3.3 Hz, 1H), 0.96 (s, 9H), 0.16 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 170.6 (0), 161.3 (0), 153.5 (0), 136.2 (1), 134.6 (0),
132.1 (0), 129.7 (1), 129.2 (1), 127.0 (1), 126.6 (1), 119.6 (1), 117.6 (1),
111.8 (0), 73.4 (1), 66.1 (1), 52.3 (3), 37.4 (2), 31.1 (2), 30.7 (2), 25.7
(3), 18.2 (0), ꢀ4.5 (3); IR (neat) ν 2929 (w), 2857 (w), 1677 (m), 1509
(m), 1250 (s), 1208 (s), 1087 (m); MS (EI) m/z 468 (20), 411 (45), 379
(50), 207 (100), 163 (70); HRMS (EI) calcd for C27H36O5Si[M]þ
468.2332, found 468.2300. Anal. Calcd for C27H36O5Si: C, 69.2; H, 7.7.
Found: C, 68.9; H, 7.6.
4-((2S,6R)-6-(4-(tert-Butyldimethylsilyloxy)phenethyl)-
5,6-dihydro-2H-pyran-2-yl)-2-nitrophenol (17d). As described
above for 17a, the title compound was obtained from 5a (318 mg, 1.0
mmol) and 6d (253 mg, 1.0 mmol) as a colorless liquid: yield 280 mg
(62%); [R]24D = þ87.2 (c 0.40, CH2Cl2); 1H NMR (300 MHz, CDCl3)
δ 10.63 (s, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.69 (dd, J = 8.6, 2.1 Hz, 1H),
7.18 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 8.4 Hz, 2H),
6.12 (ddm, J = 9.9, 4.7 Hz, 1H), 5.96 (dm, J = 10.2 Hz, 1H), 5.23 (br s,
1H), 3.41 (dddd, J = 8.6, 8.6, 4.4, 4.4 Hz, 1H), 2.65 (ddd, J = 14.2, 9.2, 5.2
Hz, 1H), 2.42 (ddd, J = 13.9, 8.2, 8.2 Hz, 1H), 2.11ꢀ2.02 (2H), 1.84
(dddd, J = 14.0, 8.8, 8.8, 5.3 Hz, 1H), 1.76ꢀ1.61 (dddd, J = 13.4, 7.5, 7.5,
4.0 Hz, 1H), 0.97 (s, 9H), 0.16 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
154.7, 153.6, 137.8, 134.3, 133.9, 133.0, 129.1, 127.4, 126.1, 124.3, 120.0,
119.7, 72.6, 66.6, 37.2, 30.9, 30.7, 25.7, 18.2, ꢀ4.5; IR (neat) ν 2928 (w),
2857 (w), 1628 (w), 1537 (m), 1509 (s), 1249 (s), 1170 (m); MS (EI)
m/z 318 (25), 211 (50), 163 (40), 133 (70), 107 (100); HRMS (EI)
calcd for C25H33NO5Si[M]þ 455.2128, found 455.2119. Anal. Calcd for
C25H33NO5Si: C, 65.9; H, 7.3. Found: C, 65.5; H, 7.5.
(þ)-2-epi-5,6-Dehydro-de-O-methylcentrolobine (4a). To
a solution of 17a (120 mg, 0.29 mmol) in THF (10 mL) was added
TBAF-trihydrate (92 mg, 0.29 mmol) at 0 °C. The mixture was stirred
for 1 h, washed with brine (5 mL), and the aqueous layer was extracted
with ethyl acetate (30 mL). The combined organic layers were dried with
MgSO4, filtered, and evaporated. The residue was purified by chroma-
tography on silica (eluent hexanes/MTBE 1:1) to give 4a (84 mg, 0.28
mmol, 97%) as colorless crystals: mp 153ꢀ155 °C; [R]24 = þ48.7
D
(c 0.37, MeOH); 1H NMR (300 MHz, CD3OD) δ 7.21 (d, J = 8.5 Hz,
2H), 6.80 (d, J = 8.6 Hz, 2H), 6.62 (d, J = 8.6 Hz, 2H), 6.53 (d, J = 8.6 Hz,
2H), 6.01 (ddd, J = 10.2, 4.6, 2.1 Hz, 1H), 5.90 (dm, J = 10.2 Hz, 1H),
5.16 (br s, 1H), 3.48 (dddd, J = 8.7, 8.7, 4.1, 4.1 Hz, 1H), 2.51 (ddd, J =
13.2, 7.8, 5.2 Hz, 1H), 2.35 (ddd, J = 13.6, 8.1, 8.1 Hz, 1H), 2.05ꢀ1.90
(2H), 1.72 (dddd, J = 13.9, 8.8, 8.8, 5.2 Hz, 1H), 1.56 (dddd, J = 12.0, 8.3,
8.3, 3.6 Hz, 1H); 13C NMR (75 MHz, CD3OD) δ 158.5 (0), 156.2 (0),
134.2 (0), 133.0 (0), 131.3 (1), 130.6 (1), 128.8 (1), 127.0 (1), 116.1
(1), 116.1 (1), 75.6 (1), 66.9 (1), 39.0 (2), 32.4 (2), 31.6 (2); IR (neat) ν
3290 (m), 2923 (w), 1612 (m), 1512 (s), 1233 (m); MS (ESI) m/z 297
([M þ H]þ, 60), 279 (100), 133 (35), 107 (40); HRMS (ESI) calcd for
C19H21O3[M þ H]þ 297.1491, found 297.1499. Anal. Calcd for
C19H20O3: C, 77.0; H, 6.8. Found: C, 76.7; H, 6.8.
Methyl-2-hydroxy-5-((2S,6R)-6-(4-hydroxyphenethyl)-
5,6-dihydro-2H-pyran-2-yl)benzoate (4c). As described above
for 4a, the title compound was obtained from 17c (130 mg, 0.28 mmol) as a
colorless liquid: yield 90 mg (89%); [R]24D = þ87.4 (c 0.36, CH2Cl2); 1H
NMR (300 MHz, CD3OD) δ 7.80 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 8.6, 2.3
Hz, 1H), 6.98 (d, J= 8.6 Hz, 2H), 6.61 (d, J= 8.5 Hz, 2H), 6.50 (d, J=8.6Hz,
2H), 6.06 (ddd, J=9.4, 4.7, 2.2 Hz, 1H), 5.91(dm, J= 10.3 Hz, 1H), 5.17 (br
s, 1H), 3.93 (s, 3H), 3.40 (dddd, J = 8.6, 8.6, 4.0, 4.0 Hz, 1H), 2.52 (ddd, J =
13.4, 7.7, 5.2 Hz, 1H), 2.34 (ddd, J = 13.8, 7.7, 7.7 Hz, 1H), 2.03ꢀ1.94 (2H),
1.72 (dddd, J = 14.0, 8.9, 8.9, 5.2 Hz, 1H), 1.60 (ddm, J = 8.4, 3.6 Hz, 1H);
13CNMR(75MHz, CD3OD, APT) δ171.8 (0), 162.6 (0), 156.3 (0), 137.6
(1), 133.9 (0), 133.4 (0), 131.0 (1), 128.1 (1), 127.8 (1), 118.7 (1), 116.0
(1),113.2 (0), 75.1 (1), 67.0 (1), 53.1 (3), 38.6 (2), 32.3 (2), 31.5 (2); IR
(neat) ν 3287 (w), 2925 (w), 1674 (m), 1514 (m), 1440 (m), 1208 (s),
1088 (m); MS (EI) m/z 354 ([M]þ, 32), 216 (45), 179 (36), 147 (37), 107
(100); HRMS (EI) calcd for C21H22O5[M]þ 354.1462, found 354.1440.
Anal. Calcd for C21H22O5: C, 71.2; H, 6.3. Found: C, 71.4; H, 6.3.
4-((2S,6R)-6-(4-Hydroxyphenethyl)-5,6-dihydro-2H-pyran-
2-yl)-2-nitrophenol (4d). As described above for 4a, the title
compound was obtained from 17d (130 mg, 0.28 mmol) as a yellowish
liquid: yield 95 mg (99%); [R]24D = þ121.3 (c 0.62, CH2Cl2); 1H NMR
(300 MHz, CD3OD) δ 7.97 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.6, 2.1 Hz,
1H), 7.14 (d, J = 8.6 Hz, 1H), 6.67 (d, J = 8.4 Hz, 2H), 6.52 (d, J = 8.5 Hz,
2H), 6.08 (dm, J = 10.2 Hz, 1H), 5.93 (dm, J = 10.3 Hz, 1H), 5.18
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(br s, 1H), 3.37 (dddd, J = 8.6, 8.6, 4.4, 4.4 Hz, 1H), 2.54 (ddd, J = 13.5,
8.1, 5.2 Hz, 1H), 2.35 (ddd, J = 13.9, 8.1, 8.1 Hz, 1H), 2.05ꢀ1.95 (2H),
1.81ꢀ1.54 (2H); 13C NMR (75 MHz, CD3OD) δ 156.3 (0), 155.3 (0),
138.5 (1), 135.2 (0), 134.8 (0), 133.8 (0), 130.3 (1), 128.3 (1), 127.5
(1), 125.5 (1), 121.1 (1), 116.0 (0), 74.2 (1), 67.5 (1), 38.4 (2), 32.1 (2),
31.5 (2); IR (neat) ν 3303 (w), 2925 (w), 1628 (m), 1537 (s), 1514 (s),
1317 (m), 1245 (s), 1172 (s); MS (EI) m/z 341 ([M]þ, 18), 323 (13),
107 (100); HRMS (EI) calcd for C19H19NO5[M]þ 341.1258, found
341.1260.
MS (EI) m/z 426 ([M]þ, 37), 369 (38), 221 (86), 121 (100); HRMS
(EI) calcd for C25H34O4Si [M]þ 426.2221, found 426.2212.
4-((1R,2S,4S,6R)-4-(4-Hydroxyphenethyl)-3,7-dioxabicy-
clo[4.1.0]heptan-2-yl)-phenol (20). As described above for 4a,
the title compound was obtained from 19 (50 mg, 0.12 mmol) as a colorless
liquid: yield 34 mg (92%); [R]24D = ꢀ18.3 (c 0.22, MeOH); 1H NMR
(300 MHz, CD3OD) δ 7.31 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H),
6.55 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 8.8 Hz, 2H), 5.05 (s, 1H), 3.53ꢀ3.45
(m, 1H), 3.38 (d, J = 4.0 Hz, 1H), 2.42 (ddd, J = 12.9, 7.4, 5.2 Hz, 1H), 2.23
(m, 1H), 1.86 (dt, J = 15.3, 4.9 Hz, 1H), 1.71 (dd, J = 15.2, 11.0 Hz, 1H),
1.64ꢀ1.35 (2H); 13C NMR (300 MHz, CD3OD) δ 159.0 (0), 156.2 (0),
134.0 (0), 131.5 (1), 130.5 (1), 129.6 (0), 116.5 (1), 116.1 (1), 73.9 (1),
63.9 (1), 52.4 (1), 52.0 (1), 39.1 (2), 31.3 (2), 30.7 (2); IR (neat) ν 3313
(w), 2915 (w), 1612 (m), 1514 (s), 1445 (m), 1225 (s), 1145 (s); MS (EI)
m/z 312 ([M]þ, 3), 147 (14), 133 (22), 120 (47), 107 (100); HRMS (EI)
calcd for C19H20O4[M]þ 312.1356, found 312.1382.
(3S,7R)-3-(4-(tert-Butyldimethylsilyloxy)phenethyl)-7-(4-hy-
droxyphenyl)tetrahydropyran-5-one (trans-21). As described
above for 17a, the title compound was obtained from 5c (180 mg, 0.54
mmol) and 6a (125 mg, 0.60 mmol) as a colorless oil: yield 192 mg (83%);
[R]24D = ꢀ13.4 (c 0.43, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.24
(d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 6.70
(d, J = 8.3 Hz, 2H), 5.41 (s, 1H), 5.23 (t, J = 5.5 Hz, 1H), 3.90 (dddd, J = 8.6,
8.6, 4.3, 4.3 Hz, 1H), 2.84ꢀ2.77 (2H), 2.70 (ddd, J = 14.5, 9.8, 5.2 Hz, 1H),
2.59ꢀ2.43 (2H), 2.36 (dd, J= 14.4, 7.8 Hz, 1H), 1.96 (dddd, J= 14.3, 9.4, 9.4,
5.3 Hz, 1H), 1.77ꢀ1.60 (m, 2H), 0.97 (s, 9H), 0.17 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 207.8 (0), 155.6 (0), 153.7 (0), 133.9 (0), 132.1 (0),
129.1 (1), 128.6 (1), 119.9 (1), 115.4 (1), 73.4 (1), 70.8 (1), 47.3 (2), 45.9
(2), 36.7 (2), 30.7 (2), 25.7 (3), 18.2 (0), ꢀ4.5 (3); IR (neat) ν 2929 (w),
2857 (w), 1712 (m), 1611 (w), 1509 (m), 1251 (s); MS (EI) m/z 426
([M]þ, 24), 369 (55), 283 (72), 163 (100); HRMS (EI) calcd for
C25H34O4Si[M]þ 426.2221, found 426.2221. Anal. Calcd for C25H34O4Si:
C, 70.4; H, 8.0. Found: C, 69.8; H, 7.9.
(3S,7R)-3-(4-Hydroxyphenethyl)-7-(4-hydroxyphenyl)tetra-
hydropyran-5-one (trans-22). As described above for 4a, the title
compound was obtained from trans-21 (150 mg, 0.35 mmol) as a viscous
colorless syrup: yield 96 mg (89%); [R]24D = ꢀ23.8 (c 0.71, CH2Cl2); 1H
NMR (300 MHz, CD3OD) δ 7.19 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.4 Hz,
2H), 6.78 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.5 Hz, 2H), 5.18 (t, J = 5.6 Hz,
1H), 3.87 (dddd, J = 8.6, 8.6, 4.3, 4.3 Hz, 1H), 2.86ꢀ2.69 (2H), 2.62 (ddd,
J = 14.1, 9.1, 5.2 Hz, 1H), 2.54ꢀ2.40 (2H), 2.34 (dd, J = 14.5, 7.7 Hz, 1H),
1.91 (dddd, J = 13.6, 8.9, 8.9, 4.2 Hz, 1H), 1.73ꢀ1.55 (m, 1H); 13C NMR
(75 MHz, CD3OD) δ 210.3 (0), 158.6 (0), 156.5 (0), 133.8 (0), 132.7 (0),
130.5 (1), 129.7 (1), 116.4 (1), 116.2 (1), 74.9 (1), 72.0 (1), 48.1 (2), 47.0
(2), 38.1 (2), 31.8 (2); IR (neat) ν 3336 (w), 2926 (w), 2488 (w), 1698
(m), 1612 (m), 1512 (s), 1225 (s), 1172 (s), 1061 (m); MS (EI) m/z 312
([M]þ, 23), 220 (65), 146 (62), 107 (100); HRMS (EI) calcd for
C19H20O4[M]þ 312.1362, found 312.1365.
2-Bromo-4-((2S,6R)-6-(4-hydroxyphenethyl)-5,6-dihydro-
2H-pyran-2-yl)phenol (4e). As described above for 4a, the title
compound was obtained from 17e (180 mg, 0.37 mmol) as a colorless
oil: yield 120 mg (86%); [R]24D = þ91.3 (c 0.375, CH2Cl2); 1H NMR
(300 MHz, CD3OD) δ 7.46 (d, J = 2.1 Hz, 1H), 7.19 (dd, J = 8.3, 2.0 Hz,
1H), 6.91 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 8.5 Hz, 2H), 6.54 (d, J = 8.6 Hz,
2H), 6.05 (ddd, J = 10.1, 4.6, 2.2 Hz, 1H), 5.90 (dm, J = 10.3 Hz, 1H), 5.15
(br s, 1H), 3.43 (dddd, J = 8.7, 8.7, 4.0, 4.0 Hz, 1H), 2.53 (ddd, J = 13.0, 7.5,
5.2 Hz, 1H), 2.37 (ddd, J = 13.6, 8.5, 8.5 Hz, 1H), 2.08ꢀ1.90 (2H), 1.73
(dddd, J = 14.0, 8.9, 8.9, 5.2 Hz, 1H), 1.59 (dddd, J = 12.2, 8.6, 8.6, 3.5 Hz,
1H); 13C NMR (75 MHz, CD3OD) δ 156.1 (0), 155.1 (0), 134.9 (0),
134.4 (1), 134.0 (0), 130.5 (1), 130.2 (1), 128.0 (1), 127.5 (1), 117.1 (1),
116.1 (1), 110.7 (0), 74.8 (1), 67.0 (1), 38.7 (2), 32.2 (2), 31.5 (2); IR
(neat) ν3278 (m), 2924 (m), 1603 (m), 1513 (s), 1221 (s), 1171 (s), 1042
(s); MS (EI) m/z 374 ([M]þ, 13), 236 (17), 199 (22), 145 (29), 107
(100); HRMS (EI) calcd for C19H19BrO3[M]þ 374.0518, found 374.0517.
Anal. Calcd for C19H19BrO3: C, 60.8; H, 5.1. Found: C, 61.1; H, 5.2.
(2S,6R)-2-(4-(40-Bromophenylcarboxy)phenethyl)-6-(4-(400-
bromophenylcarboxy)phenyl)-3,6-dihydro-2H-pyran (18). To
a solution of 4a (30 mg, 0.10 mmol) in CH2Cl2 (5.0 mL) were added Et3N
(42.0 μL, 0.30 mmol) and 4-bromobenzoyl chloride (66 mg, 0.30 mmol).
The reaction mixture was stirred at ambient temperature for 12 h. All volatiles
were evaporated, and the residue was purified by chromatography on silica
(eluent hexanes/MTBE 1:1) to give 18 (58 mg, 0.09 mmol, 88%) as colorless
crystals: mp 160ꢀ168 °C; 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 8.4
Hz, 2H), 7.99 (d, J=8.6Hz,2H), 7.62(d,J= 8.7 Hz, 2H), 7.61 (d, J=8.7Hz,
2H), 7.48 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.00 (d, J = 8.7 Hz,
2H), 6.95 (d, J = 8.7 Hz, 2H), 6.08 (ddd, J = 10.2, 4.7, 2.3 Hz, 1H), 5.31 (s,
1H), 5.99 (dm, J = 10.3 Hz, 1H), 3.51 (m, 1H), 2.74 (ddd, J = 13.5, 8.3, 5.1
Hz, 1H), 2.56 (dt, J = 13.8, 8.2 Hz, 1H), 2.17ꢀ1.99 (2H), 1.94ꢀ1.81 (1H),
1.76ꢀ1.64(1H);13CNMR(75MHz, CDCl3) δ164.5 (0), 164.4 (0), 150.3
(0), 148.7 (0), 139.7 (0), 138.8 (0), 132.4 (1), 131.9 (1), 131.9 (1), 131.7
(1), 131.6 (0), 131.6 (1), 131.6 (1), 131.1 (0), 129.7 (1), 129.5 (1), 127.1
(0), 126.3 (0), 121.4 (1), 121.2 (1), 73.7 (1), 65.9 (1), 37.2 (2), 31.1 (2),
30.8 (2); MS (ESI) m/z 662 (10), 457 (21), 359 (59), 341 (100), 313 (54);
HRMS (ESI) calcd for C33H26Br2O5[M þ H]þ 661.0225, found 661.0210.
Dihydropyran Oxide 19. To a solution of 17a (120 mg, 0.29
mmol) in CH2Cl2 (10 mL) was added m-CPBA (110 mg, 0.32 mmol) at
0 °C. The reaction mixture was allowed to warm to ambient temperature
and stirred for 12 h. It was washed with a saturated aqueous solution of
Na2SO3 (2 mL), and the aqueous layer was extracted with CH2Cl2
(30 mL). The combined organic extracts were dried with MgSO4,
filtered, and evaporated. The residue was purified by chromatography on
silica (eluent hexanes/MTBE 1:1) to give 19 (70 mg, 0.16 mmol, 55%)
as a colorless oil: [R]24D = þ7.7 (c 0.19, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 7.33 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.69 (d, J =
8.5 Hz, 2H), 6.61 (d, J = 8.5 Hz, 2H), 5.81 (s, 1H, OH), 5.19 (s, 1H),
3.53 (dd, J = 6.2, 3.3 Hz, 1H), 3.43 (d, J = 3.9, 0.5 Hz, 1H), 3.29 (ddd, J =
11.5, 8.2, 3.6 Hz, 1H), 2.55 (ddd, J = 13.8, 8.6, 5.1 Hz, 1H), 2.30 (dt, J =
13.9, 8.1 Hz, 1H), 1.88 (dd, J = 7.5, 3.0 Hz, 2H), 1.72 (dddd, J = 13.7, 8.4,
8.4, 5.1 Hz, 1H), 1.49 (dddd, J = 12.0, 8.3, 8.3, 3.6 Hz, 1H), 0.97 (s, 9H),
0.17 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 155.9 (0), 153.4 (0), 134.4
(0), 130.0 (0), 129.2 (1), 119.7 (1), 115.4 (1), 71.9 (1), 63.2 (1), 51.1
(1), 50.6 (1), 37.5 (2), 30.4 (2), 29.3 (2), 25.7 (3), 18.2 (0), ꢀ4.5 (3);
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, ana-
b
lytical data, copies of H and 13C NMR spectra. Crystallographic
1
details for compound 4a (CCDC-811748). This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: bernd.schmidt@uni-potsdam.de.
’ ACKNOWLEDGMENT
This work was generously supported by the Deutsche For-
schungsgemeinschaft (DFG-Grant Schm 1095/6-1). We thank
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ARTICLE
Evonik Oxeno for generous donations of solvents, and Umicore
(Hanau, Germany) for a generous donation of palladium(II)
acetate.
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