Enantioselective formal synthesis of (-)-podophyllotoxin from (2 S,3 R)-3-arylaziridine-2-carboxylate

Article abstract of DOI:10.1021/jo400147f

Meyers' 4-aryl-1-tetralone-lactone and ent-Zhang's 2-diarylmethyl-4- oxobutanoate were synthesized in the formal synthesis of (-)-podophyllotoxin from (2S,3R)-3-arylaziridine-2-carboxylate, via 3,3-diarylpropanoate as a common intermediate, in an overall 42% yield through 10 steps and 31% yield through 6 steps, respectively. The key steps in the synthesis were regio- and diastereoselective ring opening with an aromatic nucleophile, samarium iodide promoted reductive C-N bond cleavage, and Stille coupling for introducing the vinyl functionality. The starting aziridine was enantioselectively prepared from 3,4,5-trimethoxybenzaldehyde by guanidinium ylide mediated asymmetric aziridination. All nitrogen components used in the reaction sequence are reusable as the starting guanidinium source.

Full text of DOI:10.1021/jo400147f

Article
pubs.acs.org/joc
Enantioselective Formal Synthesis of (−)-Podophyllotoxin
from (2S,3R)‑3-Arylaziridine-2-carboxylate
Masato Takahashi, Noriyuki Suzuki, and Tsutomu Ishikawa*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba, 260-8675, Japan
S
* Supporting Information
ABSTRACT: Meyers’ 4-aryl-1-tetralone-lactone and ent-Zhang’s 2-diarylmethyl-4-oxobutanoate were synthesized in the formal
synthesis of (−)-podophyllotoxin from (2S,3R)-3-arylaziridine-2-carboxylate, via 3,3-diarylpropanoate as a common intermediate,
in an overall 42% yield through 10 steps and 31% yield through 6 steps, respectively. The key steps in the synthesis were regio-
and diastereoselective ring opening with an aromatic nucleophile, samarium iodide promoted reductive C−N bond cleavage,
and Stille coupling for introducing the vinyl functionality. The starting aziridine was enantioselectively prepared from 3,4,
5-trimethoxybenzaldehyde by guanidinium ylide mediated asymmetric aziridination. All nitrogen components used in the reaction
sequence are reusable as the starting guanidinium source.
(or unsaturated) aldehyde: a trans-aziridine is formed as the
major product when an electron-rich aldehyde is used as the
electrophile, and the coformed urea can be reused to prepare the
starting guanidinium salt. We4c,e,5 also examined the ring opening
of the generated 3-aryl (or unsaturated) aziridine-2-carboxylates
by various nucleophiles, which provided the nucleophile-inserted
2-amino-3-aryl (or unsaturated) propanoates. The 2-amino-3,
3-diarylpropanoate derivative formed by the reaction with an aromatic
(Ar) nucleophile is a suitable synthetic precursor for 4-aryltetralin-type
lignans.
In this paper we disclose new enantioselective syntheses of
Meyers’ 4-aryl-1-tetralone-lactone (2) and ent-Zhang’s 2-diaryl-
methyl-4-oxobutanoate (3), which are useful synthetic intermediates
for (−)-podophyllotoxin (1), from trans-(2S,3R)-3-arylaziridine-2-
carboxylate through the ring-opened 2-amino-3-arylpropanoate. The
key steps in the synthesis are guanidinium ylide mediated asymmetric
aziridination of 3,4,5-trimethoxybenzaldehyde, regio- and diaste-
reoselective ring opening of the generated trans-(2S,3R)-3-(3,4,
5-trimethoxyphenyl)aziridine-2-carboxylate with sesamol (3,4-methyl-
enedioxyphenol) as an Ar nucleophile, samarium iodide (SmI2)
promoted reductive C−N bond cleavage of the ring-opened 2-amino-
3,3-diarylpropanoate derivative, and Stille coupling for introducing a
vinyl functionality to the 2-hydroxy-4,5-(methylenedioxy)phenyl
substituent. In addition, each nitrogen component generated in the
aziridination and in the C−N bond cleavage reaction could be
recovered and recycled to prepare the guanidinium starting source.
INTRODUCTION
■
Lignans are a family of compounds consisting of dimerized
C6−C3 phenylpropanoids, which are biosynthetically derived from
shikimic acid via an aromatic α-amino acid such as phenylalanine
or tyrosine. Among lignans, the aryltetralin-lactone (−)-podo-
phyllotoxin (1) is an important natural product because of its
potent antitumor activity; in fact, sugar-modified analogues, such
as etoposide and etopophos, are clinically used as anticancer
drugs.1 In the stereoselective synthesis of 1 and its analogues, the
challenges are the four contiguous stereocenters and the
presence of a base-sensitive trans-lactone moiety. Although many
approaches2 to the racemic synthesis of podophyllotoxin can be
found in the literature, to the best of our knowledge, only eight
groups3 have reported its enantioselective total synthesis. Meyers
and co-workers3g used conjugate addition of 3,4,5-trimethox-
yphenyl anion to a chiral 2-naphthalenyloxazoline to construct an
aryltetralin skeleton in the asymmetric induction step and
succeeded in the first total synthesis of natural (−)-podophyllo-
toxin (1) through an aryltetralone-lactone, (−)-3-(hydroxymethyl)-
picropodophyllone (2). Recently, Zhang and co-workers3a
completed a concise total synthesis of ent-(+)-podophyllotoxin
(ent-1) by applying a tandem Michael addition−allylation of a
chirally masked 2-piperonyl anion to cinnamate and allyl bromide as
an asymmetric induction step, in which they used 2-diarylmethyl-
4-oxobutanoate 3 as a key precursor for constructing the aryltetralin
skeleton.
We4 have previously developed an atom-economical method,
applicable to asymmetric synthesis, for preparing aziridine-
2-carboxylates by reaction of a guanidinium salt with an aromatic
Received: January 25, 2013
© XXXX American Chemical Society
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Scheme 1. Retrosynthetic Analysis
through a palladium (Pd)-catalyzed coupling reaction. The benzyl-
amine obtained could be reused as the external nitrogen source in the
preparation of a starting guanidinium salt 8 by reaction with urea 9,
coproduced in the aziridination reaction, after chlorination. The
propanoate 4 could then be converted to the targeted 2 and 3 by
suitable chemical manipulations.
In our synthetic scheme, the key step is the stereoselective
construction of the C3 stereogenic center in 2-amino-3,3-
diarylpropanoates 5 by ring opening of trans-(2S,3R)-3-(3,4,5-
trimethoxyphenyl)aziridine-2-carboxylate trans-(2S,3R)-6. The
starting trans-(2S,3R)-6 was prepared in 84% yield and with 82%
enantiomeric excess (ee) by asymmetric aziridination using the
(R,R)-guanidinium salt 8 under one of our standard conditions
using tetramethylguanidine (TMG) as base,4,5 in which the diastereo-
isomeric cis-(2S,3S)-6 and urea 9 were coproduced in 4% (84% ee)
and 83% yields, respectively. In addition, the corresponding racemic
aziridines ( )-trans- and ( )-cis-6 were also prepared by using
guanidinium salt 10, which lacks phenyl pendants, under an
alternative standard condition (NaH in DMF)4,5 as a model source
for ring-opening experiments (Scheme 2).
RESULTS AND DISCUSSION
■
We observed that nonactivated N-benzyl-3-arylaziridine-
2-carboxylates were attacked exclusively at the C3 benzylic
position by electron-rich Ar nucleophiles in the presence of
indium chloride (InCl3) as a Lewis acid (LA) catalyst to give
2-benzylamino-3,3-diarylpropanoates with high diastereoselecti-
vity.5b X-ray crystallographic analysis of a ring-opened product
established that the stereochemistry of an Ar-inserted C3
stereogenic center was controlled by an anti-mode nucleophilic
opening process (inversion). Against this background, our
retrosynthetic analysis of Meyers’ 4-aryl-1-tetralone-lactone (2)
and ent-Zhang’s 2-diarylmethyl-4-oxobutanoate (3) is shown in
Scheme 1. trans-(2S,3R)-N-Benzyl-3-(3,4,5-trimethoxyphenyl)-
aziridine-2-carboxylate trans-(2S,3R)-6, prepared by an asym-
metric aziridination reaction4,5 of 3,4,5-trimethoxybenzaldehyde
(7) using the (R,R)-guanidinium salt 8, is converted to (2S,3R)-
2-benzylamino-3,3-diarylpropanoate 5 by regio- and diastereoselective
ring opening with a 4-substituted methylenedioxybenzene. Reductive
cleavage of the C−N bond in the aminopropanoate 5 provides the
propanoate 4 and benzylamine, either before or after vinylation
B
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Scheme 2. Aziridination
Scheme 3. Preliminary Examination of InCl3-Catalyzed Ring-Opening Reactions
At first, we preliminarily examined the ring-opening reaction
using the racemic trans-aziridine ( )-trans-6 with sesamol
derivatives (Scheme 3a). Treatment with sesamol benzyl ether
in the presence of a 0.5 mol amount of InCl3 afforded the desired
carbon-inserted ring-opened product ( )-11a (R = Bn) in 55%
yield with a moderate diastereomeric ratio (dr = 5.6:1). Similar
results were obtained with an allyl ether, even when the amount
of InCl3 was reduced (0.5 equiv → 0.3 equiv) (( )-11b: 60%
yield, dr = 4.3:1). Gratifyingly, the use of sesamol led to
satisfactory conversion, even with the lower amount (0.1 equiv)
of InCl3, in which the ring-opened 2-amino-3,3-diarylpropanoate
( )-11c (R = H) was provided in 91% yield, but the diastereo-
selectivity was slightly lowered (dr = 4.0:1).
phile unit from sesamol with the trimethoxybenzene derivative,
respectively, may also be possible, despite the undesired
formation of the diastereomeric ring-opened product 13 (X =
OMe) with an opposite stereochemistry at the C3 stereogenic
center. It had been reported that the 2,3,4-trimethoxyphenyl-
inserted product, not the corresponding 3,4,5-trimethoxyphenyl
derivative, was provided in the ring opening of an activated
N-tosylaziridine derivative with 1,2,3-trimethoxybenzene.6
Furthermore, we experienced unsuccessful ring opening when
anisole was used as an Ar nucleophile.5b Thus, more electron-rich
2,6-dimethoxyphenol and 2,6-dimethoxyaniline were selected as
potential 3,4,5-trimethoxyphenyl-type nucleophiles and we
comparably attempted the InCl3-catalyzed ring opening of the
methylenedioxyphenylaziridine ( )-trans-12 (Scheme 3b). However,
different from the sesamol-type nucleophiles, they functioned as
heteroatom nucleophiles, not as Ar nucleophiles, to give the
An alternative approach involving interchange of the aziridine
unit from the trimethoxyphenyl- ( )-trans-6 with the methyl-
enedioxyphenylaziridine ( )-trans-124e,f,5 and the Ar nucleo-
C
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heteroatom-inserted 2-aminopropanoate ( )-14 as a single
diastereoisomer, in place of carbon-inserted 2-amino-3,3-diaryl-
propanoates 13. In particular, the product ( )-14b (X = NH)
was provided in high yield (92%) when 2,6-dimethoxyaniline was
used as a nucleophile. These facts may suggest that a softer C6
atom of sesamol, doubly activated by two electron-donating
groups at 1,3-positions, in comparison to the phenolic oxygen
atom serves as the nucleophilic center in the ring-opening
reaction of an aziridine substrate through C−C bond formation.7
The result regarding ring opening of trimethoxyphenylazir-
idine ( )-trans-6 with sesamol prompted us to optimize an LA
catalyst (Table 1). Although conversion was slightly increased by
the replacement of InCl3 with indium triflate (In(OTf)3) or
scandium triflate (Sc(OTf)3), no improvement in dr was
observed (Table 1, entries 1−3). High dr (10:1) was attained
genation in the presence of di-tert-butyl dicarbonate ((Boc)2O).
Therefore, 2-aminopropanoate 11c was subjected to a reductive
C−N bond cleavage reaction before introduction of the C unit.
Honda and Ishikawa11 reported the SmI2-promoted C−N
bond cleavage of α-amino carbonyl compounds containing
amino esters. In this reaction, a combination of tetrahydrofuran
(THF), hexamethylphosphoric triamide (HMPA), and meth-
anol (MeOH), serving as a solvent, additive, and proton source,
respectively, played an important role in reaction completion.
However, we observed no reaction when 2-aminopropanoate
11c was subjected to Honda and Ishikawa’s condition using
MeOH as a proton source. Successful C−N bond cleavage was
accomplished by replacing MeOH with water, which provided
propanoate 18 and benzylamine in the same 93% yield (Scheme 5).
The vinyl-inserted product 4 was smoothly provided by a Pd-coupling
reaction of 18 under Stille-type conditions,8 after conversion to
trifluoromethanesulfonate 19, in better yield (90% at 50 °C for 7 h),
in comparison with the case of 2-aminopropanoate 15 (64% at 90 °C
for 8 h; Scheme 4). The ee of 4 was estimated as 81%, without the loss
of enantiopurity through reactions, and the ee could be increased to
99% after recrystallization from hexane/MeOH (10/1). This fact is
relevant to our synthetic strategy, because vinyl product 4 was the
common key precursor for Meyer’s (2) and ent-Zhang’s
intermediates (3). In trials for introduction of a C3 unit into the
deaminated product 19 under Heck reaction conditions,9 different
from the case of 2-aminopropanoates 15 and 17 (Scheme 4), the
coupling product 20 was obtained, even in moderate yield. However,
reduction of the acrylate in 20 to the allyl alcohol failed under the
conditions examined.
Table 1. Screening of LAs for the Ring Opening of the
Trimethoxyphenylaziridine ( )-trans-6 with Sesamol
( )-11c
On the basis of these experimental facts, chemical manipu-
lation of 4 toward the Meyers intermediate (2) was examined.
Straightforward preparation of tetralinol (23) and/or tetralone
systems (26) were initially attempted (Scheme 6). Direct
epoxidation of 4 under conventional conditions failed, but the
intended epoxide 21 was afforded in good yield by a stepwise
approach (93% in two steps) through iodohydrin 22, which was
provided in 95% yield by treatment of 4 with N-iodosuccinimide
(NIS) in aqueous THF. Although the diastereoselectivity in the
products was low (dr = 2:1), the newly created benzylic stereo-
genic center will be destroyed in a later conversion to a ketone.
Unfortunately, cyclization of epoxide 21 or iodohydrin 22 to tetralinol
23 was unsuccessful. Instead, indane derivative 24 displaced at the
benzylic position was obtained in approximately 30% yield. Trial
reactions for constructing the tetralone system 26 from iodo ketone
25, which was available as an unstable product from iodohydrin 22 by
Dess−Martin periodinane (DMP) oxidation, also failed.
entry
LA (amt, equiv)
conditions
yield, %
dr
1
2
3
4
5
6
7
lnCI3 (0.1)
30 °C, 4 h
30 °C, 4 h
30 °C, 4 h
30 °C, 9 h
30 °C, 9 h
0 °C, 1 h
91
93
94
89
61
85
79
4:1
ln(OTf)3 (0.3)
Sc(OTf)3 (0.1)
Zn(OTf)2 (0.1)
Cu(OTf)2 (0.1)
BF3·Et2O (1.0)
Znl2 (0.1)
4:1
4:1
10:1
10:1
4.3:1
3:1
30 °C, 24 h
with zinc triflate [Zn(OTf)2] or copper triflate [Cu(OTf)2], and
in the former case, the high conversion (89%) was maintained
(Table 1, entries 4 and 5). On the other hand, boron trifluoride
etherate (BF3·Et2O) or zinc iodide (ZnI2) led to unsatisfactory
results (Table 1, entries 6 and 7). Thus, we selected Zn(OTf)2
as the most suitable LA catalyst for the sesamol-participated
ring opening and obtained the same results when the enantio-
rich aziridine trans-(2S,3R)-6 was applied to the ring-opening
reaction.
Next, we attempted to introduce a vinyl unit into the sesamol-
inserted 2-amino-3-arylpropanoate 11c, derived from trans-
(2S,3R)-6, by Pd-catalyzed coupling before reductive C−N
cleavage (Scheme 4). After the phenolic function in 11c was
activated by making trifluoromethanesulfonate, the N-benzyl
(N-Bn) derivative 15 was subjected to a Stille-type reaction.8
Coupling product 16 was afforded in moderate yield; however,
subsequent reductive C−N cleavage of 16 under the optimized
conditions discussed later was unsatisfactory (4: 30%, see Scheme 5).
Independent trials for introduction of a C3 unit under Heck9
or Sonogashira10 reaction conditions as alternative approaches to
the Meyers intermediate (2) were attempted. However, starting
materials were mainly recovered in both coupling reactions using
either the N-Bn (15) or N-(tert-butoxycarbonyl) (N-Boc)
derivative (17), which was derived from 15 by catalytic hydro-
Therefore, we applied a stepwise approach to the tetralin
systems (Scheme 7). After protection of the alcohol group of 22
with a tert-butyldimethylsilyl (TBS) group, treatment of the silyl
ether 27 with lithium hexamethyldisilazide (LHMDS) in the
presence of HMPA afforded the desired cyclized tetralin 28 in
90% yield as expected. The 1H NMR spectrum showed that the
2:1 dr of starting material 22 was preserved in product 28,
indicating that highly stereocontrolled ring closure occurred;
however, the relative stereochemistry between C3 and C4
configurations (numbering based on tetralin-1-ol) could not be
1
assigned because of complex signal patterns in the H NMR
spectrum. After deprotection, oxidation of tetralinol 23 with
DMP provided the corresponding ketone 26 as a single isomer in
92% yield. The desired cyclization from protected iodohydrin 27
to tetralinol system 28 with a trans-(3R,4R) configuration was
deduced by comparison with the coupling constant between
C3−H and C4−H (J = 8.0 Hz) in tetralone system 26.12 Aldol
D
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Scheme 4. Trials for Introducing a C Unit into 2-Amino-3,3-diarylpropanoates
condensation of 26 with excess formalin solution smoothly
provided (−)-3-(hydroxymethyl)picropodophyllone (2),
Meyers’ intermediate, in 95% yield. Product data were identical
with reported data,3g and the overall yield was 35% from a
commercially available 3,4,5-trimethoxybenzaldehyde (7) through
11 steps with an average 91% yield. On the other hand, Meyers and
co-workers synthesized the intermediate 2 in overall 10% yield
from piperonal through 19 steps with an average yield of 89%.
Finally, synthesis of ent-Zhang’sintermediate(3)fromacommon
precursor (vinyl-inserted product 4) was attempted (Scheme 8).
Alkylation with allyl bromide provided 2-diarylmethyl-4-pentenoate
29 in 92% yield with a 3:1 dr. Oxidative cleavage of two vinyl
functions with an osmium tetraoxide (OsO4) and sodium periodate
(NaIO4) system proceeded smoothly to give the desired
2-diarylmethyl-4-oxobutanoate (3), ent-Zhang’s intermediate, in
49% isolated yield after purification of the diastereoisomeric
dicarbonyl compounds obtained. These findings indicate that the
major diastereoisomer of the pentenoate 29 was the 2S deriva-
tive. The data on the product 3 were identical with the reported data,
except for a specific rotation,3a and the overall yield was 26% from
3,4,5-trimethoxybenzaldehyde (7) through seven steps with an
average yield of 84%. The synthetic efficiency was almost
comparable to that of Zhang’s route (overall 34% yield from
bromopiperonal through four steps with an average yield of 78%).
atoms are not incorporated into the products, but the nitrogen
components (urea and benzylamine) released during the
reaction sequence can be recovered and reused to prepare the
guanidinium starting material. In addition, not only is the
aziridine system likely analogous to an aromatic α-amino acid
derivativea biosynthetic precursor of phenylpropanoid as a
monomeric lignan componentbut it might also contribute
greatly to controlling the new stereogenic center of the diaryl-
substituted carbon in the ring-opened product. Thus, this
approach provides a new strategy for the synthesis of biologically
important 4-aryltetralin lignans.
EXPERIMENTAL SECTION
■
Melting points were determined with a melting point hot-stage
instrument and are uncorrected. 1H and 13C NMR spectra were
recorded with 400 and 600 MHz spectrometers in CDCl3. FAB and ESI
mass spectra were obtained using a double-focusing magnetic sector
mass spectrometer and time-of-flight mass spectrometer, respectively.
For column and flash chromatography silica gel 60 (63-210 μm) and
NH-coated silica gel (100−200 mesh) and silica gel 60 (40−100 μm),
respectively, were used. All reactions were carried out using dry solvents
under an argon atmosphere, and organic extracts were evaporated under
reduced pressure after drying over MgSO4, unless otherwise noted.
Asymmetric Aziridination of 3,4,5-Trimethoxybenzaldehyde
(7) and (R,R)-Guanidinium Bromide (8). A freshly distilled TMG
(0.4 mL, 3.20 mmol) was added dropwise to a stirred solution of 7
(0.589 g, 3.00 mmol) and 8 (1.732 g, 3.146 mmol) in THF (3.0 mL) at
0 °C. The mixture was stirred at room temperature for 1 day, and then
SiO2 (30 g) was added after dilution with CHCl3 (30 mL). The resulting
slurry was stirred at room temperature for 1 day. The SiO2 was filtered
through Celite and washed with AcOEt. After evaporation of the filtrate,
column chromatography of the residue (SiO2, AcOEt/hexane 1/6) gave
trans-(2S,3R)-6 (1.01 g, 84%, 82% ee), cis-(2S,3S)-6 (43 mg, 4%, 84% ee),
and urea 9 (colorless prisms (692 mg, 83%), mp 149−151 °C).
CONCLUSION
■
We effectively achieved the enantioselective syntheses of Meyers’
4-aryl-1-tetralone-lactone and ent-Zhang’s 2-diarylmethyl-4-
oxobutanoate as useful synthetic intermediates for (−)-podophyllotoxin
from trans-(2S,3R)-3-(3,4,5-trimethoxyphenyl)aziridine-2-carboxylate,
which was derived from 3,4,5-trimethoxybenzaldehyde by
guanidinium ylide mediated asymmetric aziridination. This
strategy may appear to have low atom economy because nitrogen
trans-(2S,3R)-tert-Butyl 3-(3,4,5-trimethoxyphenyl)aziridine-2-
carboxylate (trans-(2S,3R)-6): colorless needles, mp 130−133 °C;
E
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Scheme 5. Introduction of a C Unit after Reductive C−N Bond Cleavage
[α]27D = +1.3° (c 1.00, CHCl3); IR (ATR) 1719 cm−1; 1H NMR (400
MHz) δ 1.40 (s, 9H), 2.69 (d, J = 2.2 Hz, 1H), 3.21 (d, J = 2.2 Hz, 1H),
3.82 (s, 3H), 3.84 (s, 6H), 4.08 (d, J = 14.0 Hz, 1H), 4.23 (d, J = 14.0 Hz,
1H), 6.53 (s, 2H), 7.24 (t, J = 6.0 Hz, 1H), 7.31 (t, J = 7.4 Hz, 2H), 7.40
(d, J = 7.2 Hz, 2H); 13C NMR (100 MHz) δ 28.0, 45.7, 48.1, 54.6, 56.1,
60.8, 81.8, 103.0, 126.9, 128.1, 128.2, 134.1, 137.3, 139.2, 153.3, 167.6;
HPLC (CHIRALCEL OD-H, λ 254 nm, hexane/iPrOH 100/1, flow
rate 1.0 mL/min) tR for a major isomer 12.1 min, tR for a minor isomer
17.9 min. Anal. Calcd for C23H29NO5: C, 69.15; H, 7.32; N, 3.51. Found:
C, 69.37; H, 7.38; N, 3.51.
cis-(2S,3S)-tert-Butyl 3-(3,4,5-trimethoxyphenyl)aziridine-2-car-
boxylate (cis-(2S,3S)-6): colorless oil; [α]27D = +3.3° (c 1.09, CHCl3);
IR (ATR) 1731 cm−1; 1H NMR (400 MHz) δ 1.21 (s, 9H), 2.53 (d, J =
7.0 Hz, 1H), 2.93 (d, J = 7.0 Hz, 1H), 3.52 (d, J = 13.8 Hz, 1H), 3.80 (s,
3H), 3.83 (s, 6H), 4.03 (d, J = 13.8 Hz, 1H), 6.63 (s, 2H), 7.26−7.46 (m,
5H); 13C NMR (100 MHz) δ 27.8, 46.8, 47.1, 56.0, 60.7, 63.1, 81.0,
104.6, 127.1, 127.9, 128.3, 131.1, 137.0, 137.9, 152.7, 167.0; HRMS
(FAB) calcd for C23H30NO5 400.2124, found 400.2123; HPLC
(CHIRALCEL OD-H, λ 254 nm, hexane/iPrOH 50/1, flow rate 1.0
mL/min) tR for a major isomer 15.6 min, tR for a minor isomer 13.5 min.
( )-tert-Butyl 2-Benzylamino-3-(2-benzyloxy-4,5-methyle-
nedioxyphenyl)-3-(3,4,5-trimethoxyphenyl)propanoate
(( )-11a). A solution of ( )-trans-6 (104 mg, 0.259 mmol), InCl3
(27 mg, 0.122 mmol), and sesamol benzyl ether (68 mg, 0.297 mmol) in
CH2Cl2 (1.2 mL) was stirred at 35 °C for 2 h, quenched by addition of
saturated NaHCO3 solution (2 mL), and extracted with AcOEt (10 mL ×3).
The combined organic solutions were washed with H2O (1 mL × 2) and
brine (1 mL × 2), dried, and evaporated. Column chromatography of the
residue (SiO2, hexane/AcOEt 4/1) gave ( )-11a (89 mg, 55%, dr 5.6/1),
which was recrystallized from hexane/Et2O (1/1) to give a single isomer
(60 mg, 37%) as colorless prisms, mp 125−126 °C: IR (ATR) 3676,
1721 cm−1; 1H NMR (400 MHz) δ 1.18 (s, 9H), 3.61 (d, J = 13.4 Hz,
1H), 3.63 (s, 6H) 3.75 (s, 3H), 3.77 (d, J = 10.5 Hz, 1H), 3.85 (d, J =
13.4 Hz, 1H), 4.48 (d, J = 10.5 Hz, 1H), 4.85 (d, J = 11.5 Hz, 1H), 4.94
(d, J = 11.5 Hz, 1H), 5.89 (d, J = 1.5 Hz, 1H), 5.94 (d, J = 1.5 Hz, 1H),
6.38 (s, 2H), 6.54 (s, 1H), 6.73 (s, 1H), 7.23−7.33 (m, 10H); 13C NMR
(100 MHz) δ 27.7, 47.6, 51.9, 55.8, 60.7, 64.1, 71.1, 80.8, 96.0, 101.0,
106.1, 107.6, 122.4, 127.0, 127.4, 127.8, 128.2, 128.4, 128.5, 136.4, 136.8,
137.0, 139.6, 141.3, 146.3, 151.4, 152.6, 173.8; HRMS (FAB) calcd for
C37H42NO8 628.2911, found 628.2889. Anal. Calcd for C37H42NO8: C,
70.79; H, 6.58; N, 2.23. Found: C, 70.67; H, 6.60; N, 2.26.
( )-tert-Butyl 2-Benzylamino-3-(2-allyloxy-4,5-methylene-
dioxyphenyl)-3-(3,4,5-trimethoxyphenyl)propanoate
(( )-11b). A solution of ( )-trans-6 (101 mg, 0.252 mmol), InCl3 (18
mg, 0.08 mmol), and sesamol allyl ether (195 mg, 1.10 mmol) in CH2Cl2
(1.0 mL) was stirred at 30 °C for 3.5 h, quenched by addition of saturated
NaHCO3 solution (2 mL), and extracted with AcOEt (15 mL × 3). The
combined organic solutions were washed with H2O (1 mL × 2) and brine
(1 mL × 2), dried, and evaporated. Column chromatography of the
residue (SiO2, hexane/AcOEt 4/1) gave ( )-11b (87 mg, 60%, dr 4.3/1),
which was recrystallized from hexane/Et2O (1/1) to give a single isomer
(46 mg, 32%) as colorless prisms, mp 113−114 °C: IR (ATR) 3676, 1721
cm−1; 1H NMR (400 MHz) δ 1.20 (s, 9H), 3.61 (d, J = 13.4 Hz, 1H),
3.75−3.81 (m, 10H), 3.84 (d, J = 13.4 Hz, 1H), 4.32−4.46 (m, 2H), 4.52
(d, J = 10.6 Hz, 1H), 5.19−5.40 (m, 2H), 5.88 (d, J = 1.5 Hz, 1H), 5.92 (d,
J = 1.5 Hz, 1H), 5.92−6.03 (m, 1H), 6.47 (s, 1H), 6.49 (s, 2H), 6.71 (s,
1H), 7.16−7.33 (m, 5H); 13C NMR (100 MHz,) δ 27.8, 51.9, 56.1, 60.7,
64.4, 65.8, 70.1, 80.9, 96.2, 101.5, 106.2, 107.7, 117.2, 122.7, 127.0, 128.2,
F
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Scheme 6. Chemical Manipulation Trials for Preparation of 4-Aryltetralin Systems
Scheme 7. Preparation of Meyers’ Intermediate 2
128.4, 133.5, 136.7, 139.8, 141.3, 146.4, 146.4, 151.4, 152.7, 173.9. Anal.
Calcd for C33H39NO8: C, 68.61; H, 6.80; N, 2.42. Found: C, 68.56; H,
6.80; N, 2.29.
(2S,3R)-tert-Butyl 2-Benzylamino-3-(2-hydroxy-4,5-methy-
lenedioxyphenyl)-3-(3,4,5-trimethoxyphenyl)propanoate (11c).
A solution of trans-(2S,3R)-6 (50 mg, 0.125 mmol), Zn(OTf)2 (4 mg,
G
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Scheme 8. Preparation of ent-Zhang’s Intermediate 3
0.011 mmol), and sesamol (21 mg, 0.153 mmol) in CH2Cl2 (1.2 mL)
was stirred at 30 °C for 9 h, quenched by addition of saturated NaHCO3
solution (2 mL), and extracted with AcOEt (15 mL × 3). The combined
organic solutions were washed with H2O (5 mL × 2) and brine (5 mL × 2),
dried, and evaporated. Column chromatography of the residue (SiO2,
hexane/AcOEt 6/1) gave 11c (60 mg, 89%, dr 10/1) as colorless prisms,
mp 145−147 °C, which were twice washed with hexane/Et2O (1/1):
[α]27D = +17.1° (c 1.09, CHCl3); IR (ATR) 3278, 1722 cm−1; 1H NMR
(400 MHz) δ 1.29 (s, 9H,), 3.48 (d, J = 13.4 Hz, 1H), 3.54 (d, J = 13.4
Hz, 1H), 3.80 (s, 6H), 3.82 (s, 3H), 3.84 (d, J = 5.6 Hz, 1H), 4.41 (d, J =
5.6 Hz, 1H), 5.85 (s, 2H), 6.42 (s, 1H), 6.52 (s, 1H), 6.56 (s, 2H), 7.09
(d, J = 6.8 Hz, 2H), 7.25−7.55 (m, 3H); 13C NMR (100 MHz) δ 27.7,
52.2, 54.4, 56.0, 60.9, 64.8, 82.6, 100.3, 100.9, 105.5, 111.2, 115.7, 127.7,
128.1, 128.7, 134.8, 136.8, 137.4, 140.2, 147.8, 152.4, 153.3, 170.1;
HRMS (FAB) calcd for C30H36NO8 538.2441, found 538.2427.
Ring Opening of the Methylenedioxyphenylaziridine
( )-trans-12 with 2,6-Dimethoxyphenol. A mixture of ( )-trans-
12 (102 mg, 0.290 mmol), InCl3 (6 mg, 0.029 mmol), and 2,6-
dimethoxyphenol (67 mg, 0.433 mmol) in CH2Cl2 (3 mL) was stirred at
40 °C for 14 h, quenched by addition of saturated NaHCO3 solution
(1 mL), and extracted with AcOEt (15 mL × 3). The combined organic
solutions were washed with H2O (1 mL × 2) and brine (1 mL × 2),
dried, and evaporated. Column chromatography of the residue (SiO2,
hexane/AcOEt 8/1) gave 2-aminopropanoate ( )-14a (32 mg, 22%)
and the isomerized cis-aziridine ( )-cis-12 (32 mg, 31%).
1H), 6.63 (dd, J = 8.1, 1.5 Hz, 1H), 6.69 (t, J = 8.2 Hz, 1H), 6.73 (d,
J = 1.5 Hz, 1H), 7.24−7.27 (m, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.44 (d, J =
7.5 Hz, 2H); 13C NMR (100 MHz) δ 28.1, 53.1, 55.8, 60.0, 66.1, 81.4,
100.6, 104.7, 107.5, 107.9, 119.3, 121.0, 125.8, 127.0, 128.27, 128.29,
133.8, 140.4, 146.4, 147.1, 150.6, 171.9; HRMS (ESI) calcd for
C29H34N2NaO6 529.2315, found 529.2334.
tert-Butyl 2-Benzylamino-3-[4,5-methylenedioxy-2-(trifluoro-
methanesulfonyloxy)phenyl]-3-(3,4,5-trimethoxyphenyl)-
propanoate (15). Tf2O (0.2 mL, 1.17 mmol) was added dropwise to
a stirred solution of 11c (416 mg, 0.773 mmol) and pyridine (0.1 mL,
1.24 mmol) in CH2Cl2 (4.0 mL) at 0 °C, and the mixture was stirred at
0 °C for 5 h. After addition of saturated NaHCO3 solution (10 mL), the
mixture was extracted with AcOEt (30 mL × 3). The combined organic
solutions were washed with H2O (5 mL × 2) and brine (5 mL × 2),
dried, and evaporated. Column chromatography of the residue (SiO2,
hexane/AcOEt 8/1) gave 15 (436 mg, 84%) as colorless prisms, mp
1
133−134 °C: IR (ATR) 1726 cm−1; H NMR (400 MHz) δ 1.26 (s,
9H), 3.62 (d, J = 13.5 Hz, 1H), 3.64 (d, J = 9.9 Hz, 1H), 3.78 (s, 3H),
3.80 (s, 6H), 3.85 (d, J = 13.5 Hz,1H), 4.39 (d, J = 9.9 Hz, 1H), 6.00 (d,
J = 1.3 Hz, 1H), 6.05 (d, J = 1.3 Hz, 1H), 6.52 (s, 2H), 6.73 (s, 1H), 6.78
(s, 1H), 7.16−7.32 (m, 5H); 13C NMR (100 MHz) δ 27.7, 47.1, 51.6,
56.1, 60.7, 64.5), 81.5, 102.4, 102.6, 105.9, 108.0, 116.9, 120.0, 127.1,
128.2, 135.0, 137.1, 139.3, 141.3, 146.8, 147.3, 153.0, 172.7; HRMS
(ESI) calcd for C31H34F3NNaO10S 692.1753, found 692.1733.
tert-Butyl 2-Benzylamino-3-(4,5-methylenedioxy-2-vinyl-
phenyl)-3-(3,4,5-trimethoxyphenyl)propanoate (16). Tributylvi-
nyltin (0.1 mL, 0.342 mmol) was added dropwise to a stirred mixture of
15 (200 mg, 0.299 mmol), Pd(PPh3)4 (35 mg, 0.030 mmol), and LiCl
(25 mg, 0.599 mmol) in DMF (3.0 mL) at room temperature, and the
mixture was stirred at 90 °C for 8 h. After addition of 10% KF solution
(2 mL), the mixture was stirred for 30 min and filtered through Celite,
which was washed with AcOEt (10 mL). After separation of the organic
solution the aqueous solution was extracted with AcOEt (20 mL × 2).
The combined organic solutions were washed with H2O (2 mL × 2) and
brine (2 mL × 2), dried, and evaporated. Column chromatography of
the residue (SiO2, hexane/AcOEt 6/1) gave 16 (105 mg, 64%) as
( )-tert-Butyl 2-benzylamino-3-[(2,6-dimethoxyphenyl)oxy]-3-
(3,4-methylenedioxyphenyl)propanoate (( )-14a): colorless oil; IR
(ATR) 1729 cm−1; 1H NMR (400 MHz) δ 1.20 (s, 9H), 3.658 (s, 6H),
3.660 (d, J = 6.7 Hz, 1H), 3.78 (d, J = 13.0 Hz, 1H), 3.94 (d, J = 13.0 Hz,
1H), 5.30 (d, J = 6.7 Hz, 1H), 5.90 (s, 2H), 6.44 (d, J = 8.4 Hz, 2H), 6.66
(d, J = 8.1 Hz, 1H), 6.83 (dd, J = 8.1, 1.6 Hz, 1H), 6.88 (t, J = 8.4 Hz,
1H), 7.09 (d, J = 1.6 Hz, 1H), 7.18−7.36 (m, 5H); 13C NMR (100
MHz) δ 27.7, 52.4, 55.7, 67.9, 80.8, 84.5, 100.7, 105.2, 107.1, 109.1,
122.0, 123.5, 126.7, 128.2, 128.3, 132.9, 135.8, 140.3, 146.8, 147.1, 153.2,
171.2; HRMS (ESI) calcd for C29H34NO7 508.2335, found 508.2318.
( )-cis-tert-Butyl 3-(3,4-methylenedioxyphenyl)aziridine-2-car-
1
boxylate (( )-cis-12): mp 176−178 °C; IR (ATR) 1731 cm−1; H
1
colorless prisms, mp 145−147 °C: IR (ATR) 3671, 1716 cm−1; H
NMR (400 MHz) δ 1.24 (s, 9H), 2.48 (d, J = 7.0 Hz, 1H), 2.93 (d, J = 6.8
Hz, 1H), 3.53 (d, J = 14.0 Hz, 1H), 3.96 (d, J = 14.0 Hz, 1H), 5.90 (s,
2H), 6.71 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H),
7.22−7.44 (m, 5H); 13C NMR (100 MHz) δ 27.8, 46.8, 47.1, 63.3, 81.1,
100.8, 107.7, 108.6, 121.2, 127.1, 127.8, 128.3, 129.3, 138.0, 146.7, 147.0,
167.2; HRMS (ESI) calcd for C21H23NaNO4 376.1525, found 376.1522.
NMR (400 MHz) δ 1.22 (s, 9H), 3.58 (d, J = 13.0 Hz, 1H), 3.73 (d, J =
9.9 Hz, 1H), 3.77 (s, 3H), 3.78 (s, 6H), 3.81 (d, J = 13.0 Hz, 1H), 4.39
(d, J = 9.9 Hz, 1H), 5.22 (dd, J = 10.8, 1.3 Hz, 1H), 5.45 (dd, J = 17.2, 1.3
Hz, 1H), 5.92 (d, J = 1.5 Hz, 1H), 5.97 (d, J = 1.5 Hz, 1H), 6.43 (s, 2H),
6.80 (s, 1H), 6.92 (s, 1H), 7.05 (dd, J = 17.2, 10.8 Hz, 1H), 7.18−7.33
(m, 5H); 13C NMR (100 MHz) δ 27.8, 49.3, 52.0, 56.1, 60.8, 65.1, 81.2,
101.0, 106.0, 106.5, 107.2, 115.4, 127.0, 128.2, 128.4, 131.6, 132.3, 134.6,
136.5, 139.5, 146.4, 147.4, 152.9, 173.5; HRMS (ESI) calcd for
C32H38NO7 548.2648, found 548.2666.
tert-Butyl 2-(tert-Butoxycarbonylamino)-3-[4,5-methylene-
dioxy-2-(trifluoromethanesulfonyloxy)phenyl]-3-(3,4,5-
trimethoxyphenyl)propanoate (17). A mixture of 15 (202 mg,
0.301 mmol), Pd/C (21 mg), and Boc2O (0.15 mL, 0.653 mmol) in
AcOEt (2.0 mL) was vigorously stirred at room temperature for 6 h
under a hydrogen atmosphere. The mixture was filtered through Celite,
which was washed with AcOEt. After evaporation of the filtrate, column
chromatography of the residue (SiO2, hexane/AcOEt 4/1) gave 17 (204
mg, 100%) as colorless prisms, mp 65−67 °C: IR (ATR) 3649, 1734,
1716 cm−1; 1H NMR (400 MHz) δ 1.22 (s, 9H), 1.35 (s, 9H), 3.80 (s,
(
)-tert-Butyl 2-Benzylamino-3-[(2,6-dimethoxyphenyl)-
amino]-3-(3,4-methylenedioxyphenyl)propanoate (( )-14b). A
mixture of ( )-trans-12 (64 mg, 0.181 mmol), InCl3 (2 mg, 0.01 mmol),
and 2,6-dimethoxyaniline (27 mg, 0.178 mmol) in CH2Cl2 (1.0 mL) was
stirred at room temperature for 1.5 h, quenched by addition of saturated
NaHCO3 solution (3 mL), and extracted with AcOEt (5 mL × 3). The
combined organic solutions were washed with H2O (2 mL × 2) and
brine (2 mL × 2), dried, and evaporated. Column chromatography of
the residue (SiO2, hexane/AcOEt 4/1) gave ( )-14b (83 mg, 92%) as
colorless prisms, mp 97−99 °C: IR (ATR) 3334, 1711 cm−1; 1H NMR
(400 MHz) δ 1.41 (s, 9H), 3.63 (d, J = 4.0 Hz, 1H), 3.66 (d, J = 13.1 Hz,
1H), 3.82 (s, 6H), 3.91 (d, J = 13.1 Hz, 1H), 5.25 (br s, 1H), 5.71 (br, 1H,
exchangeable), 5.82 (s, 2H), 6.45 (d, J = 8.2 Hz, 2H), 6.58 (d, J = 8.1 Hz,
H
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3H), 3.83 (s, 6H), 4.44 (d, J = 9.9 Hz, 1H), 4.90 (t, J = 9.9 Hz, 1H), 4.97
(d, J = 9.5 Hz, 1H), 6.01 (s, 2H), 6.56 (s, 2H), 6.72 (s, 1H), 7.03 (s, 1H);
13C NMR (100 MHz) δ 27.5, 28.1, 47.6, 56.0, 56.8, 60.8, 80.1, 82.1,
102.5, 102.8, 105.6, 108.1, 115.3, 117.4, 119.5, 121.6, 127.0, 133.8, 137.3,
140.9, 147.3, 147.6, 153.1, 155.1, 170.3; HRMS (FAB) calcd for
C29H36F3NNaO12S 702.1808, found 702.1779.
(t, J = 8.0 Hz, 1H), 5.26 (dd, J = 11.2, 1.3 Hz, 1H), 5.51 (dd, J = 17.2, 1.3
Hz, 1H), 5.92 (d, J = 1.5 Hz, 1H), 5.93 (d, J = 1.5 Hz, 1H), 6.41 (s, 2H),
6.66 (s, 1H), 6.96 (s, 1H), 7.09 (dd, J = 17.2, 11.2 Hz, 1H); 13C NMR
(100 MHz) δ 27.9, 42.1, 42.5, 56.1, 60.8, 80.7, 101.0, 104.8, 106.3, 107.2,
115.2, 130.4, 134.3, 134.7, 136.5, 138.8, 146.3, 147.5, 153.1, 170.9;
HRMS (ESI) calcd for C25H30NaO7 465.1889, found 465.1878; HPLC
(CHIRALCEL OD-H, λ 254 nm, hexane/iPrOH 9/1, flow rate 1.0 mL/
min) tR for the major isomer 9.3 min, tR for the minor isomer 10.9 min.
trans-Methyl 2-[2-(tert-Butoxycarbonyl)-1-(3,4,5-
trimethoxyphenyl)ethyl]-4,5-methylenedioxyphenyl-
propenoate (20). Methyl acrylate (0.05 mL, 0.555 mmol) was added
dropwise to a stirred mixture of 19 (50 mg, 0.0893 mmol), Pd(PPh3)4
(17 mg, 0.015 mmol), and NaHCO3 (39 mg, 0.458 mmol) in DMF
(1.0 mL) at room temperature, and the mixture was stirred at 120 °C for
24 h. After addition of H2O (2 mL), the mixture was extracted with
AcOEt (15 mL × 3). The combined organic solutions were washed with
H2O (2 mL × 3) and brine (2 mL × 3), dried, and evaporated. Column
chromatography of the residue (SiO2, hexane/AcOEt 3/1) gave 20
(27 mg, 61%) as colorless prisms, mp 168−170 °C: IR (ATR) 1717 cm−1;
1H NMR (400 MHz) δ 1.31 (s, 9H), 2.85 (dd, J = 15.2, 8.1 Hz, 1H), 2.92
Reductive C−N Bond Cleavage of Aminopropanoate 11c. A
0.1 M solution of SmI2 in THF (125 mL, 12.3 mmol) was prepared
with CH2I2 (1.0 mL, 12.3 mmol), Sm (2.132 g, 14.2 mmol), and THF
(125 mL) at room temperature. To the solution were successively added
HMPA (2.2 mL, 12.4 mmol), H2O (0.3 mL, 16.7 mmol), and a solution
of 11c (1.36 g, 2.52 mmol) in THF (7 mL), and the mixture was stirred
at room temperature for 1 h and then for 10 min in air after addition of
H2O (20 mL). The precipitates were removed by filtration through
Celite and repeatedly washed with AcOEt. After evaporation of the
combined filtrates, the residue was diluted with AcOEt (200 mL). The
organic solution was washed with 10% HCl solution (20 mL × 3), H2O
(10 mL × 2), and brine (10 mL × 2), dried, and evaporated. Column
chromatography of the residue (SiO2, hexane/AcOEt 3/1) gave 18
(1.01 g, 93%). The aqueous layer was made alkaline (pH >12) by
addition of 10% NaOH solution and extracted with AcOEt (50 mL × 2).
The combined organic solutions were washed with H2O (10 mL × 2)
and brine (10 mL × 2), dried (K2CO3), and evaporated. Column
chromatography of the residue (NH-SiO2, hexane/CHCl3 1/1) gave
BnNH2 (250 mg, 93%) as a colorless oil.
(R)-tert-Butyl 3-(2-hydroxy-4,5-methylenedioxyphenyl)-3-(3,4,5-tri-
methoxyphenyl)propanoate (18): colorless needles, mp 175−177 °C;
[α]27D = −22.2° (c 1.01, CHCl3); IR (ATR) 3422, 1716 cm−1; 1H NMR
(400 MHz) δ 1.39 (s, 9H), 2.92 (dd, J = 16.4, 10.4 Hz, 1H), 3.02 (dd, J =
16.4, 4.8 Hz, 1H), 3.82 (s, 3H), 3.83 (s, 6H), 4.66 (dd, J = 10.4, 4.8 Hz,
1H), 5.85 (d, J = 1.4 Hz, 1H), 5.86 (d, J = 1.4 Hz, 1H), 6.43 (s, 2H), 6.45
(s, 1H), 6.48 (s, 1H), 6.70 (s, 1H); 13C NMR (100 MHz) δ 27.9, 39.1,
41.4, 56.1, 60.8, 82.0, 100.0, 101.0, 104.8, 107.2, 123.2, 136.6, 139.0,
141.8, 146.4, 148.0, 153.2, 173.4. Anal. Calcd for C23H28O8: C, 63.88; H,
6.53. Found: C, 63.50; H, 6.56.
(dd, J = 15.2, 8.1 Hz, 1H), 3.78 (s, 3H), 3.80 (s, 3H), 3.81 (s, 6H), 4.79
(t, J = 8.1 Hz, 1H), 5.98 (d, J = 1.3 Hz, 1H), 5.99 (d, J = 1.3 Hz, 1H), 6.18
(d, J = 15.7 Hz, 1H), 6.41 (s, 1H), 6.79 (s, 1H), 7.01 (s, 1H), 8.17 (d, J =
15.7 Hz, 1H); 13C NMR (100 MHz) δ 27.9, 42.2, 42.8, 51.6, 56.1, 60.8,
80.9, 101.5, 104.7, 106.4, 107.2, 118.0, 126.8, 136.5, 137.8, 138.4, 141.8,
146.6, 149.6, 153.2, 167.3, 170.4; HRMS (FAB) calcd for C27H32O9
500.2046, found 500.2043.
tert-Butyl 3-[4,5-Methylenedioxy-2-(oxacyclopropyl)-
phenyl]-3-(3,4,5-trimethoxyphenyl)propanoate (21). A solution
of 4 (100 mg, 0.226 mmol) and NIS (61 mg, 0.270 mmol) in THF/H2O
(4/1, 1.0 mL) was stirred at room temperature for 4 h. After addition of
K2CO3 (81 mg, 0.589 mmol) and MeOH (1.0 mL), the mixture was
stirred at room temperature for 1 h, quenched by addition of saturated
Na2S2O3 solution (1 mL), and extracted with AcOEt (20 mL × 2). The
combined organic solutions were washed with H2O (1 mL × 2), dried,
and evaporated to give 21 (97 mg, 93%, dr 2/1) as pale yellow needles,
mp 78−82 °C, which were used in the next reaction without further
purification: IR (ATR) 1717 cm−1; 1H NMR (400 MHz) for the major
isomer δ 1.33 (s, 9H), 2.39 (dd, J = 5.7, 2.7 Hz, 1H), 2.92 (d, J = 8.1 Hz,
2H), 2.95 (dd, J = 5.7, 4.1 Hz, 1H), 3.79 (s, 6H), 3.803 (s, 3H), 4.12 (dd,
J = 4.1, 2.7 Hz, 1H), 4.74 (t, J = 8.1 Hz, 1H), 5.92−5.95 (m, 2H), 6.38 (s,
2H), 6.758 (s, 1H), 6.79 (s, 1H); 1H NMR (400 MHz) for the minor
isomer δ 1.31 (s, 9H), 2.70 (dd, J = 5.8, 2.7 Hz, 1H), 2.88 (dd, J = 8.0, 7.0
Hz, 2H), 3.17 (dd, J = 5.8, 4.2 Hz, 1H), 3.801 (s, 6H), 3.81 (s, 3H), 4.01
(dd, J = 4.2, 2.7 Hz, 1H), 4.75 (t, J = 8.0 Hz,1H), 5.92−5.95 (m, 2H),
6.46 (s, 2H), 6.75 (s, 1H), 6.762 (s, 1H); 13C NMR (100 MHz) for the
major isomer δ 27.9, 42.2, 42.6, 50.3, 50.4, 56.1, 60.8, 80.8, 101.1, 104.8,
105.4, 106.9, 129.34, 135.1, 136.6, 138.9, 146.4, 147.25, 153.1, 170.78;
13C NMR (100 MHz) for the minor isomer δ 27.9, 42.3, 42.5, 50.3, 50.4,
(R)-tert-Butyl 3-[4,5-Methylenedioxy-2-(trifluoromethane-
sulfonyloxy)phenyl]-3-(3,4,5-trimethoxyphenyl)propanoate
(19). Tf2O (0.03 mL, 0.175 mmol) was added dropwise to a stirred
solution of 18 (50 mg, 0.116 mmol) and pyridine (0.03 mL, 0.372
mmol) in CH2Cl2 (1.2 mL) at −40 °C, and the mixture was stirred at
0 °C for 1 h. After addition of saturated NaHCO3 solution (1 mL), the
mixture was extracted with AcOEt (15 mL × 2). The combined organic
solutions were washed with H2O (1 mL) and brine (1 mL × 2), dried,
and evaporated. Column chromatography of the residue (SiO2, hexane/
AcOEt 6/1) gave 19 (60 mg, 92%) as a colorless oil: [α]25D = −10.4°
1
(c 1.02, CHCl3); IR (ATR) 1718 cm−1; H NMR (400 MHz) δ 1.32
(s, 9H), 2.81 (dd, J = 15.2, 7.8 Hz, 1H), 2.89 (dd, J = 15.2, 8.8 Hz, 1H),
3.81 (s, 3H), 3.83 (s, 6H), 4.72 (t, J = 8.2 Hz, 1H), 6.01 (d, J = 1.2 Hz,
1H), 6.02 (d, J = 1.2 Hz, 1H), 6.48 (s, 2H), 6.74 (s, 1H), 6.75 (s, 1H);
13C NMR (100 MHz) δ 27.6, 40.4, 41.4, 56.0, 60.7, 80.8, 102.4, 102.8,
104.7, 107.5, 116.8, 120.0, 129.9, 136.8, 136.9, 140.1, 146.8, 147.5, 153.1,
169.8; HRMS (ESI) calcd for C24H27F3NaO10S 587.1175, found
587.1151.
(R)-tert-Butyl 3-(4,5-Methylenedioxy-2-vinylphenyl)-3-(3,4,5-
trimethoxyphenyl)propanoate (4). Tributylvinyltin (0.5 mL, 1.71
mmol) was added dropwise to a stirred solution of 19 (769 mg, 1.36
mmol), Pd(dppf)Cl2·CH2Cl2 (110 mg, 0.135 mmol), and LiCl (118 mg,
2.79 mmol) in DMF (7.7 mL) at room temperature, and the mixture was
stirred at 50 °C for 7 h. After addition of 10% KF solution (5 mL), the
mixture was stirred at room temperature for 30 min and filtered through
Celite, which was washed with AcOEt. After separation of the organic
solution the aqueous solution was extracted with AcOEt (50 mL × 2).
The combined organic solutions were washed with H2O (5 mL × 2) and
brine (5 mL × 2), dried, and evaporated. Column chromatography of
the residue (SiO2, hexane/AcOEt 6/1) gave 4 (541 mg, 90%, 81% ee) as
colorless needles, mp 115−116 °C, which were twice recrystallized from
hexane/MeOH (10/1) to give optically pure 4 (338 mg, 56%, 99% ee)
as colorless needles, mp 115−116 °C: [α]25D = −20.2° (c 1.02, CHCl3);
IR (ATR) 1717 cm−1; 1H NMR (400 MHz) δ 1.31 (s, 9H), 2.81 (dd, J =
15.3, 7.7 Hz, 1H), 2.88 (dd, J = 15.3, 8.4 Hz, 1H), 3.80 (s, 9H), 4.72
56.1, 60.7, 80.7, 101.1, 104.9, 105.4, 107.0, 129.28, 135.2, 136.7, 138.5,
146.3, 147.27, 153.2, 170.81; HRMS (ESI) calcd for C25H30NaO8
481.1838, found 481.1840.
(R)-tert-Butyl 3-{2-[(1-Hydroxy-2-iodo)ethyl]-4,5-methylene-
dioxyphenyl}-3-(3,4,5-trimethoxyphenyl)propanoate (22). A
solution of 4 (200 mg, 0.452 mmol) and NIS (121 mg, 0.537 mmol)
in THF/H2O (4/1, 2.0 mL) was stirred at room temperature for 7 h in
air, quenched by addition of saturated Na2S2O3 solution (1 mL), and
extracted with AcOEt (20 mL × 2). The combined organic solutions
were washed with saturated Na2S2O3 solution (1 mL), H2O (1 mL × 2),
and brine (1 mL × 2), dried, and evaporated. Column chromatography
of the residue (SiO2, hexane/AcOEt 3/1) gave 22 (253 mg, 95%, dr
2/1) as colorless prisms, mp 182−184 °C: [α]25.5 = +22.1° (c 1.08,
D
CHCl3); IR (ATR) 3508, 1723 cm−1; 1H NMR (400 MHz) for the major
isomer δ 1.32 (s, 9H), 2.71 (dd, J = 10.3, 3.2 Hz, 1H), 2.90 (d, J = 8.0 Hz,
2H), 3.00 (d, J = 2.4 Hz, 1H, exchangeable), 3.13 (t, J = 9.8 Hz, 1H), 3.796
(s, 3H), 3.83 (s, 6H), 4.61 (t, J = 8.0 Hz, 1H), 5.30 (dt, J = 9.3, 3.2 Hz, 1H),
5.96 (s, 2H), 6.40 (s, 2H), 6.81 (s, 1H), 7.00 (s, 1H); 1H NMR (400 MHz)
for the minor isomer δ 1.34 (s, 9H), 2.57 (d, J = 3.1 Hz, 1H, exchangeable),
2.89 (d, J = 8.0 Hz, 2H), 3.30 (t, J = 10.0 Hz, 1H), 3.55 (dd, J = 10.3, 3.0 Hz,
1H), 3.803 (s, 3H), 3.81 (s, 6H), 4.54 (t, J = 8.0 Hz, 1H), 5.11 (dt, J = 9.6,
I
dx.doi.org/10.1021/jo400147f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2.8 Hz, 1H), 5.96 (s, 2H), 6.37 (s, 2H), 6.83 (s, 1H), 7.03 (s, 1H); 13CNMR
(100 MHz) for the major isomer δ 13.1, 27.9, 42.2, 42.8, 56.2, 60.8, 70.1,
81.1, 101.2, 104.6, 106.0, 106.6, 133.0, 133.5, 136.7, 139.0, 146.5, 147.5,
153.3, 171.1; 13C NMR (100 MHz) for the minor isomer δ 13.9, 27.9, 42.4,
42.5, 56.1, 60.7, 70.9, 81.0, 101.2, 104.8, 106.4, 107.2, 133.0, 133.2, 136.7,
138.6, 146.5, 147.4, 153.2, 170.8; HRMS (ESI) calcd for C25H31IKO8
625.0701, found 625.0709.
gun under reduced pressure for 1 h. A 1.6 M solution of LHMDS in THF
(0.1 mL, 0.16 mmol) was added dropwise to a stirred solution of 27 (65
mg, 0.092 mmol, dr 2/1) and HMPA (0.05 mL, 0.282 mmol) in THF
(1.0 mL) at −78 °C, and the mixture was stirred at −78 °C for 10 h. After
addition of saturated NH4Cl solution (1 mL) at −78 °C, the mixture was
extracted with AcOEt (20 mL × 2). The combined organic solutions
were washed with H2O (1 mL × 2) and brine (1 mL × 2), dried, and
evaporated. Column chromatography of the residue (SiO2, hexane/
2-(tert-Butoxycarbonyl)-3-hydroxymethyl-5,6-methylene-
dioxy-1-(3,4,5-trimethoxyphenyl)indane (24). The reaction flask
was dried by heat gun under reduced pressure for 1 h. A 1.6 M solution
of LiHMDS in THF (0.16 mL, 0.256 mmol) was added dropwise to a
stirred solution of epoxide 21 (50 mg, 0.109 mmol) in THF (2.2 mL) at
−78 °C, and the mixture was stirred at −78 °C for 18 h. After addition of
saturated NH4Cl solution (1 mL) at 0 °C, the mixture was extracted with
AcOEt (20 mL × 2). The combined organic solutions were washed with
H2O (1 mL × 2) and brine (1 mL × 2), dried, and evaporated. Column
chromatography of the residue (SiO2, hexane/AcOEt 3/1) gave 24 (15
mg, 30%) as a colorless needles, mp 66−68 °C: IR (ATR) 3504, 1723
AcOEt 6/1) gave 28 (47 mg, 90%, dr 2/1) as colorless needles, mp 69−
1
74 °C: [α]26.5 = +34.0° (c 1.04, CHCl3); IR (ATR) 1727 cm−1; H
D
NMR (400 MHz) for the major isomer δ 0.18 (s, 3H), 0.24 (s, 3H), 0.98
(s, 9H), 1.27 (s, 9H), 1.96−2.11 (m, 2H), 2.82 (ddd, J = 13.2, 11.2, 2.0
Hz, 1H), 3.78 (s, 3H), 3.795 (s, 6H), 4.09−4.15 (m, 1H), 4.94 (dd, J =
11.2, 4.8 Hz, 1H), 5.86−5.90 (m, 2H), 6.22 (s, 1H), 6.33 (s, 2H), 6.95 (s,
1H); 1H NMR (400 MHz) for the minor isomer δ 0.15 (s, 3H), 0.18 (s,
3H), 0.92 (s, 9H), 1.32 (s, 9H), 2.25 (dd, J = 5.3, 2.6 Hz, 1H), 2.28 (dd,
J = 5.5, 2.4 Hz, 1H), 3.18 (dt, J = 10.7, 3.4 Hz, 1H), 3.799 (s, 3H), 3.83 (s,
6H), 4.09−4.15 (m, 1H), 4.75 (t, J = 3.7 Hz, 1H), 5.86−5.90 (m, 2H),
6.32 (s, 1H), 6.37 (s, 2H), 6.67 (s, 1H); 13C NMR (100 MHz) for the
major isomer δ −4.68, −3.92, 18.1, 25.9, 27.8, 36.7, 49.2, 49.5, 56.1, 60.9,
69.6, 80.5, 100.8, 106.0, 106.3, 108.8, 131.8, 133.6, 136.8, 139.5, 146.3,
146.6, 153.1, 173.1; 13C NMR (100 MHz) for the minor isomer δ −4.45,
−4.26, 18.0, 25.8, 27.9, 35.1, 45.0, 47.9, 56.0, 60.8, 67.7, 80.2, 101.0, 106.2,
108.1, 109.3, 131.7, 132.0, 136.9, 139.5, 145.9, 147.2, 153.0, 174.5; HRMS
(ESI) calcd for C31H44NaO8Si 595.2703, found: 595.2707.
(1R,2R)-2-(tert-Butoxylcarbonyl)-4-hydroxy-6,7-methylene-
dioxy-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydronaphtha-
lene (23). A 1.0 M solution of TBAF in THF (0.67 mL, 0.67 mmol) was
added to a solution of 28 (192 mg, 0.335 mmol, dr 2/1) in THF (3 mL)
at room temperature, and the mixture was stirred at the same
temperature for 8 h in air. After addition of H2O (3 mL), the mixture
was extracted with AcOEt (30 mL × 2). The combined organic solutions
were washed with H2O (2 mL × 2) and brine (2 mL × 2), dried, and
evaporated. Column chromatography of the residue (SiO2, hexane/
AcOEt 3/1) gave 23 (139 mg, 90%, dr 2/1) as colorless needles, mp 65−
67 °C: [α]25D = +24.6° (c 0.97, CHCl3); IR (ATR) 3733, 1717 cm−1; 1H
NMR (400 MHz) for the major isomer δ 1.31 (s, 9H), 2.01 (ddd, J =
13.2, 10.0, 8.0 Hz, 1H), 2.35 (ddd, J = 13.2, 6.0, 3.2 Hz, 1H), 2.45 (d, J =
8.8 Hz, 1H), 2.85 (ddd, J = 10.0, 8.4, 3.2 Hz, 1H), 3.78 (s, 6H), 3.83 (s,
3H), 4.22 (d, J = 8.0 Hz, 1H), 4.80−4.86 (m, 1H), 5.90 (d, J = 1.2 Hz,
1H), 5.91 (d, J = 1.2 Hz, 1H), 6.26 (s, 2H), 6.39 (s, 1H), 7.08 (s, 1H); 1H
NMR (400 MHz) for the minor isomer δ 1.25 (s, 9H), 1.89 (d, J = 4.0
Hz, 1H), 2.13 (ddd, J = 13.6, 12.3, 3.2 Hz, 1H), 2.24 (dt, J = 13.6, 3.2 Hz,
1H), 3.13 (ddd, J = 12.3, 11.0, 2.8 Hz, 1H), 3.80 (s, 6H), 3.84 (s, 3H),
4.01 (d, J = 10.4 Hz, 1H), 4.80−4.86 (m, 1H), 5.90 (s,2H), 6.30 (s, 2H),
6.31 (s, 1H), 6.81 (s, 1H); 13C NMR (150 MHz) for the major isomer δ
27.9, 34.48, 48.0, 48.7, 56.15, 60.87, 67.8, 81.0, 101.0, 106.1, 106.9,
108.9, 130.9, 132.8, 136.80, 139.5, 146.7, 147.1, 153.1, 173.9; 13C NMR
(150 MHz) for the minor isomer δ 27.8, 34.52, 44.6, 49.3, 56.17, 60.89,
67.1, 80.4, 101.1, 106.5, 108.5, 109.2, 130.4, 132.6, 136.85, 139.1, 146.4,
147.7, 153.1, 174.2; HRMS (ESI) calcd for C25H30NaO8 481.1838,
found 481.1824.
1
cm−1; H NMR (400 MHz) δ 1.45 (s, 9H), 3.10 (t, J = 9.2 Hz, 1H),
3.47−3.54 (m,1H), 3.81 (s, 6H), 3.85 (s, 3H), 3.96 (dd, J = 11.2, 6.2 Hz,
1H), 4.06 (dd, J = 11.2, 4.2 Hz, 1H), 4.48 (d, J = 9.2 Hz, 1H), 5.92 (d, J =
1.3 Hz, 1H), 5.95 (d, J = 1.3 Hz, 1H), 6.40 (s, 1H), 6.43 (s, 2H), 6.74 (s,
1H); 13C NMR (100 MHz) δ 28.1, 49.9, 53.6, 56.1, 59.2, 60.8, 65.3, 81.4,
101.2, 103.6, 105.3, 105.6, 133.9, 136.9, 138.2, 139.4, 147.5, 147.7, 153.2,
173.6; HRMS (ESI) calcd for C25H30NaO8 481.1838, found 481.1827.
tert-Butyl 3-(2-Iodoacetyl-4,5-methylenedioxyphenyl)-3-
(3,4,5-trimethoxyphenyl)propanoate (25). A mixture of 22 (50 mg,
0.085 mmol), DMP (54 mg, 0.128 mmol), and NaHCO3 (22 mg,
0.256 mmol) in CH2Cl2 (0.9 mL) was stirred at room temperature for
4 h. After addition of saturated NaHCO3 solution (1 mL) with ice
cooling, the mixture was extracted with AcOEt (20 mL × 2). The
combined organic solutions were washed with H2O (1 mL × 2) and
brine (1 mL × 2), dried, and evaporated. Column chromatography of
the residue (SiO2, hexane/AcOEt 4/1) gave 25 (43 mg, 85%) as labile
13
1
colorless prisms, mp 116−118 °C: H NMR (400 MHz) δ 1.31 (s,
9H), 2.85 (dd, J = 15.6, 8.8 Hz, 1H), 2.93 (dd, J = 15.6, 7.3 Hz, 1H), 3.80
(s, 3H), 3.83 (s, 6H), 4.23 (d, J = 10.8 Hz, 1H), 4.30 (d, J = 10.8 Hz, 1H),
5.05 (t, J = 8.1 Hz, 1H), 5.99 (d, J = 1.3 Hz, 1H), 6.01 (d, J = 1.3 Hz, 1H),
6.53 (s, 2H), 6.78 (s, 1H), 7.04 (s, 1H).
(R)-tert-Butyl 3-{2-[1-(tert-Butyldimethylsilyloxy)-2-iodoethyl]-
4,5-methylenedioxyphenyl}-3-(3,4,5-trimethoxyphenyl)-
propanoate (27). TBSOTf (0.03 mL, 0.128 mmol) was added to a
stirred solution of 22 (50 mg, 0.086 mmol, dr 2/1) and 2,6-lutidine
(0.03 mL, 0.259 mmol) in CH2Cl2 (0.9 mL) at 0 °C, and the mixture was
stirred at room temperature for 8 h. After addition of saturated NaHCO3
solution (1 mL) at 0 °C, the mixture was extracted with AcOEt
(20 mL × 2). The combined organic solutions were washed with H2O
(1 mL × 2) and brine (1 mL × 2), dried, and evaporated. Column
chromatography of the residue (SiO2, hexane/AcOEt 6/1) gave 27
(55 mg, 92%, dr 2/1) as a colorless oil: [α]26 = +104.1° (c 0.954,
D
1
CHCl3); IR (ATR) 1731 cm−1; H NMR (400 MHz) for the major
isomer δ −0.08 (s, 3H), 0.21 (s, 3H), 0.91 (s, 9H), 1.35 (s, 9H), 2.77−
2.93 (m, 4H), 3.783 (s, 3H), 3.83 (s, 6H), 4.52 (t, J = 7.8 Hz, 1H), 5.15
(dd, J = 9.6, 1.7 Hz, 1H), 5.96 (d, J = 1.5 Hz, 1H), 5.99 (d, J = 1.5 Hz,
1H), 6.35 (s, 2H), 6.87 (s, 1H), 7.00 (s, 1H); 1H NMR (400 MHz) for
the minor isomer δ −0.24 (s, 3H), 0.10 (s, 3H), 0.79 (s, 9H), 1.35 (s,
9H), 2.34 (dd, J = 10.2, 1.9 Hz, 2H), 3.15 (dd, J = 10.4, 9.6 Hz, 1H), 3.57
(dd, J = 10.4, 2.0 Hz, 1H), 3.78 (s, 3H), 3.81 (s, 6H), 4.36 (dd, J = 9.4, 6.5
Hz, 1H), 4.96 (dd, J = 9.6, 2.0 Hz, 1H), 5.96 (d, J = 1.5 Hz, 1H), 6.01 (d,
J = 1.5 Hz, 1H), 6.37 (s, 2H), 6.88 (s, 1H), 7.06 (s, 1H); 13C NMR (100
MHz) for the major isomer δ −4.77, −4.63, 14.3, 18.2, 25.8, 28.0, 43.1,
43.4, 56.2, 60.9, 71.0, 80.8, 101.1, 104.6, 106.3, 107.0, 132.0, 135.4,
136.7, 139.3, 146.4, 147.1, 153.4, 170.6; 13C NMR (100 MHz) for the
minor isomer δ −5.43, −3.61, 14.1, 18.1, 25.7, 28.0, 43.0, 43.3, 56.1,
60.7, 67.9, 80.9, 101.1, 105.3, 106.2, 106.7, 131.4, 135.8, 136.8, 138.6,
146.3, 147.0, 153.4, 170.5; HRMS (ESI) calcd for C31H45INaO8Si
723.1826, found 723.1849.
(1R,2R)-2-(tert-Butoxylcarbonyl)-6,7-methylenedioxy-1-
(3,4,5-trimethoxyphenyl)-2,3-dihydro-4(1H)-naphthalenone
(26). A mixture of 23 (52 mg, 0.114 mmol, dr 2/1), DMP (66 mg, 0.155
mmol), and NaHCO3 (25 mg, 0.299 mmol) in CH2Cl2 (1.1 mL) was
stirred at room temperature for 3 h. After addition of saturated NaHCO3
solution (1 mL) with ice cooling, the mixture was extracted with AcOEt
(20 mL × 2). The combined organic solutions were washed with H2O
(1 mL × 2) and brine (1 mL × 2), dried, and evaporated. Column
chromatography of the residue (SiO2, hexane/AcOEt 4/1) gave 26
(48 mg, 92%) as colorless prisms, mp 116−118 °C: [α]23 = +41.7°
D
(c 1.01, CHCl3); IR (ATR) 1721, 1666 cm−1; 1H NMR (400 MHz) δ
1.24 (s, 9H), 2.78 (dd, J = 17.0, 4.6 Hz, 1H), 2.87 (dd, J = 17.0, 9.0 Hz,
1H), 3.22 (ddd, J = 9.0, 8.0, 4.6 Hz, 1H), 3.79 (s, 6H), 3.84 (s, 3H), 4.40
(d, J = 8.0 Hz, 1H), 6.00 (br s, 1H), 6.01 (br s, 1H), 6.34 (s, 2H), 6.41 (s,
1H), 7.52 (s, 1H); 13C NMR (100 MHz) δ 27.7, 38.7, 48.6, 49.3, 56.2,
60.9, 81.4, 101.8, 105.8, 106.1, 108.8, 127.2, 136.9, 137.2, 140.8, 147.4,
152.5, 153.3, 171.8, 193.9; HRMS (ESI) calcd for C25H28NaO8
479.1682, found 479.1664.
(1R,2R)-2-(tert-Butoxylcarbonyl)-4-(tert-butyldimethylsily-
loxy)-6,7-methylenedioxy-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-
tetrahydronaphthalene (28). The reaction flask was dried by heat
J
dx.doi.org/10.1021/jo400147f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Preparation of Meyers’ Intermediate 2. A mixture of 26 (30 mg,
0.066 mmol), 37% HCHO solution (1.0 mL), and 1 N NaOH solution
(0.14 mL, 0.14 mmol) in THF (1.0 mL) was stirred at room
temperature for 1 day in air. After addition of saturated NH4Cl
solution (1 mL), the mixture was extracted with AcOEt (20 mL × 2).
The combined organic solutions were washed with H2O (1 mL × 2)
and brine (1 mL × 2), dried, and evaporated. Column chroma-
tography of the residue (SiO2, hexane/AcOEt 3/1) gave 2 (28 mg,
95%) as colorless prisms, mp 106−108 °C (lit.3g mp 105−108 °C):
[α]25 = −23.9° (c 0.98, CHCl3) (lit.3g [α]23 = −23.7° (c 0.38,
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving NMR spectra for compounds 2−4, trans-(2S,3R)-
and cis-(2S,3S)-6, ( )-11a,b, 11c, ( )-cis-12, ( )-14a,b, and
1
15−29 (only H NMR spectrum for 25) and HPLC traces for
( )-trans- and trans-(2S,3R)-6, ( )-cis- and cis-(2S,3S)-6, and
( )- and (R)-4. This material is available free of charge via the
Internet at http://pubs.acs.org.
D
D
CHCl3)); IR (ATR) 3505, 2921, 1770, 1659, 1593, 1474 cm−1; H
NMR (400 MHz) δ 3.26 (br d, J = 11.4 Hz, 1H), 3.36 (d, J = 2.2 Hz,
1H), 3.64 (d, J = 11.4 Hz, 1H), 3.74 (s, 6H), 3.81 (s, 3H), 4.35 (d, J =
9.4 Hz, 1H), 4.59 (d, J = 9.4 Hz, 1H), 4.78 (d, J = 2.2 Hz, 1H), 6.07 (s,
1H), 6.10 (s, 1H), 6.15 (s, 2H), 6.70 (s, 1H), 7.47 (s, 1H); 13C NMR
(100 MHz) δ 42.8, 48.0, 54.0, 56.3, 60.9, 64.2, 72.7, 102.3, 105.1,
106.3, 109.7, 127.2, 137.3, 137.9, 138.8, 148.6, 153.6, 154.0, 176.0,
196.8; HRMS (ESI) calcd for C23H22NaO9 465.1162, found
465.1157.
1
AUTHOR INFORMATION
Corresponding Author
*E-mail: benti@faculty.chiba-u.jp
Notes
■
The authors declare no competing financial interest.
REFERENCES
■
(1) (a) Guerram, M.; Jiang, Z.-Z.; Zhang, L.-Y. Chin. J. Nat. Med. 2012,
10, 161−169. (b) Xu, H.; Lu, M.; Tian, X. Curr. Med. Chem. 2009, 16,
327−349. (c) Gordaliza, M.; Garcia, P. A.; del Corral, J. M.; Castro, M.
A.; Gomez-zurita, M. A. Toxicon 2004, 44, 441−459. (d) Canel, C.;
Moraes, R. M.; Dayan, F. E.; Ferreira, D. Phytochemistry 2000, 54, 115−
120. (e) Hartwell, J. L.; Schrecker, A. W. J. Am. Chem. Soc. 1951, 73,
2909−2916.
tert-Butyl 2-Allyl-3-(4,5-methylenedioxy-2-vinylphenyl)-3-
(3,4,5-trimethoxyphenyl)propanoate (29). The reaction flask was
dried by heat gun under reduced pressure for 1 h. A 1.6 M solution of
LHMDS in THF (0.15 mL, 0.24 mmol) was added dropwise to a stirred
solution of 4 (50 mg, 0.113 mmol) in THF (2.2 mL) at −78 °C, and the
mixture was stirred at −78 °C for 30 min. After addition of allyl bromide
(0.03 mL, 0.344 mmol) at −78 °C, the mixture was stirred at −78 °C for
1 h and then at room temperature for 2.5 h. After addition of saturated
NH4Cl solution (2 mL) with ice cooling, the mixture was extracted with
AcOEt (15 mL × 3). The combined organic solutions were washed with
H2O (1 mL × 2) and brine (1 mL × 2), dried, and evaporated. Column
chromatography of the residue (SiO2, hexane/AcOEt 6/1) gave 29
(50 mg, 92%, dr 3/1) as a colorless oil: IR (ATR) 1724 cm−1; 1H NMR
(400 MHz) for the major isomer δ 1.19 (s, 9H), 2.24 (t, J = 7.0 Hz, 1H),
3.05−3.15 (m, 1H), 3.79 (s, 3H), 3.83 (s, 6H), 4.27 (d, J = 11.6 Hz, 1H),
4.96−5.05 (m, 2H), 5.27 (dd, J = 10.9, 1.2 Hz, 1H), 5.44 (dd, J = 17.1,
1.2 Hz, 1H), 5.67−5.81 (m, 1H), 5.88 (d, J = 1.3 Hz, 1H), 5.92 (d, J =
1.3 Hz, 1H), 6.47 (s, 2H), 6.87 (s, 1H), 6.97 (s, 1H), 7.19 (dd, J =
17.1, 10.9 Hz, 1H); 1H NMR (400 MHz) for the minor isomer δ 1.21
(s, 9H), 2.24 (t, J = 7.0 Hz, 1H), 3.05−3.15 (m, 1H), 3.76 (s, 3H),
3.83 (s, 6H), 4.39 (d, J = 11.7 Hz, 1H), 4.96−5.05 (m, 2H), 5.30 (dd,
J = 10.7, 1.2 Hz, 1H), 5.44 (dd, J = 16.8, 1.2 Hz, 1H), 5.67−5.81 (m,
1H), 5.90 (d, J = 1.2 Hz, 1H), 5.95 (d, J = 1.2 Hz, 1H), 6.51 (s, 2H),
6.80 (s, 1H), 6.92 (s, 1H), 7.18−7.22 (m, 1H); 13C NMR (100 MHz)
for the major isomer δ 27.7, 36.0, 48.5, 51.5, 56.1, 60.7, 80.5, 100.9,
105.0, 106.6, 106.9, 115.4, 116.8, 130.8, 134.1, 135.04, 135.1, 136.60,
137.4, 146.2, 147.3, 153.2, 172.7; 13C NMR (100 MHz) for the minor
isomer δ 27.8, 35.6, 48.0, 51.4, 56.0, 60.7, 80.6, 101.1, 105.2, 106.2,
106.5, 115.6, 116.8, 131.3, 133.5, 134.8, 134.96, 136.56, 138.2, 146.3,
147.8, 152.9, 173.5; HRMS (ESI) calcd for C28H34NaO7 505.2202,
found 505.2188.
(2) (a) Mingoia, F.; Vitale, M.; Madec, D.; Prestat, G.; Poli, G.
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Preparation of ent-Zhang’s Intermediate 3. A solution of 29
(31 mg, 0.064 mmol, dr 3/1), NaIO4 (82 mg, 0.384 mmol), and 0.1 M
OsO4 solution (0.06 mL, 0.006 mmol) in 1,4-dioxane/H2O (4/1,
2.0 mL) was stirred at 50 °C for 8 h in air, quenched by addition of
saturated Na2S2O3 solution (2 mL) with ice cooling, and extracted with
AcOEt (15 mL × 3). The combined organic solutions were washed with
H2O (1 mL × 2) and brine (1 mL × 2), dried, and evaporated. Column
chromatography of the residue (SiO2, hexane/AcOEt 6/1) gave 3
(15 mg, 49%) as a colorless oil: [α]D27 +94.74° (c 1.03, CHCl3) (lit.3a
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RHF/6-31G shows that the phenolic oxygen atom is the most electron
rich position.
27
1
[α]D = −95.38° (c 1.66, CHCl3)); IR (ATR) 1724, 1676 cm−1; H
NMR (400 MHz) δ 1.19 (s, 9H), 2.60 (dd, J = 18.3, 3.7 Hz, 1H), 2.88
(ddd, J = 18.3, 10.0, 1.3 Hz, 1H), 3.56−3.64 (m, 1H), 3.79 (s, 3H), 3.84
(s, 6H), 5.23 (d, J = 11.7 Hz, 1H), 6.02 (d, J = 1.6 Hz, 1H), 6.06 (d, J =
1.6 Hz, 1H), 6.52 (s, 2H), 7.14 (s, 1H), 7.24 (s, 1H), 9.67 (s, 1H), 10.3
(s, 1H); 13C NMR (100 MHz) δ 27.5, 44.9, 45.5, 45.6, 56.2, 60.7, 81.3,
102.1, 105.1, 108.3, 110.2, 128.2, 136.1, 137.2, 141.2, 146.9, 152.2, 153.5,
172.2, 189.6, 199.4; HRMS (ESI) calcd for C26H30NaO9 509.1788,
found 509.1773.
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K
dx.doi.org/10.1021/jo400147f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(11) Honda, T.; Ishikawa, F. Chem. Commun. 1999, 1065−1066.
(12) In the corresponding ethyl ester series, a larger coupling constant
(J = 7.5 Hz) for the trans derivative12a and a smaller constant (J = 4.7 Hz)
for the cis derivative12b were reported: (a) Pohmakotr, M.; Komutkul,
T.; Tuchinda, P.; Prabpai, S.; Kongsaeree, P.; Reutrakul, V. Tetrahedron
2005, 61, 5311−5321. (b) Kaneko, T.; Wong, H. S. L. Eur. Pat.
EP0224938, 1987-06-10.
(13) Only 1H NMR data for the structure assignment are given, due to
its instability.
L
dx.doi.org/10.1021/jo400147f | J. Org. Chem. XXXX, XXX, XXX−XXX