Total synthesis of (+)-isatisine A: Application of a silicon-directed mukaiyama-type [3 + 2]-annulation

Article abstract of DOI:10.1021/acs.joc.5b00051

Complete details of an asymmetric synthesis of (+)-isatisine A (1) are described. The synthesis highlights the use of a highly diastereoselective Mukaiyama-type [3 + 2]-annulation of allylsilane 5 with the unsaturated aldehyde 9a to assemble the functiona

Full text of DOI:10.1021/acs.joc.5b00051

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Total Synthesis of (+)-Isatisine A: Application of a Silicon-Directed
Mukaiyama-Type [3 + 2]-Annulation
Jihoon Lee and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library Development, Metcalf Center for Science and
Engineering, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
S
* Supporting Information
ABSTRACT: Complete details of an asymmetric synthesis of
(+)-isatisine A (1) are described. The synthesis highlights the
use of a highly diastereoselective Mukaiyama-type [3 + 2]-
annulation of allylsilane 5 with the unsaturated aldehyde 9a to
assemble the functionalized tetrahydrofuran core of isatisine A.
A convergent route to the framework of the natural product
was established that employed a substrate-controlled indole
coupling that was followed by a late-stage intramolecular
copper(I)-mediated amidation to complete the assembly of the
tetracyclic framework of (+)-isatisine A. In addition, the scope
of the [3 + 2]-annulation was evaluated and enhanced utilizing diastereomeric allylsilanes anti-5 and syn-5 to establish an efficient
route to stereochemically well-defined tetrahydrofurans.
Isatisine A (1) is a unique fused-polycyclic alkaloid bearing
an indole ring system at the C2 position, of which the
intriguing and challenging structure led to significant attention
from the synthetic community. In 2010, Kerr and co-worker
reported the first total synthesis of (+)-isatisine A and revision
of its absolute configuration.2a,b This report was followed by
two total syntheses from the Panek2c and Liang2d groups,
respectively. Recently, Xie2e has disclosed a biomimetic total
synthesis of isatisine A, and shortly after, Ramana and co-
workers2f,g reported their efforts culminating in the synthesis of
the natural product and its derivatives.
INTRODUCTION
■
Isatis indigotica Fort. (Cruciferae), which is a plant species
widely cultivated in China and East Asia, has been used as a
traditional medicine for treatment of viral diseases such as
influenza, viral pneumonia, mumps, and hepatitis. Further
investigations conducted by Chen and co-workers on I.
Indigotica to identify potent antiviral compounds resulted in
the isolation of isatisne A (1, Figure 1) along with 11 other
The present work differs considerably from the previous
syntheses. For instance, Kerr and co-worker also reported a [3
+ 2] cycloaddition using a vinyl cyclopropane and an aldehyde
to generate the tetrahydrofuran core. However, the indole
addition to the intermediate aminal turned out to be
problematic, which led to a revised route to introduce the
indole branch through a cascade reaction sequence including
incorporation of indole and lactamization to form the
tetracyclic framework of isatisine at the late stage of their
synthesis. Additionally, the independent approaches, reported
by Xie and Ramana, respectively, demonstrated the use of the
“chiral pool” where protected forms of D-glucal and D-ribose
were used as the starting materials, respectively.
Figure 1. Structures of isatisine A (1) and its acetonide derivative 2.
nonalkaoid species.1 Initially, isatisine was isolated as an
acetonide derivative, which was most certainly generated during
the chromatographic purification using acetone as an eluent.
However, its unusual dioxolane group that is rarely found in
natural products led to further investigation to unambiguously
assign the correct structure of the natural product. Biological
evaluation of acetonide derivative of isatisine revealed its potent
cytotoxicity against C8166 with CC50 = 302 μM and anti-HIV
activity of EC50 = 37.8 μM.
Herein, we disclose the full details of our efforts toward the
total synthesis of (+)-isatisine A (1), including the development
of Mukaiyama-type [3 + 2]-annulation that led to the assembly
of the tetrahydrofuran core and the synthesis of 9-H-13-silyl-
substituted advanced intermediate 15.
Received: January 9, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00051
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described.4 However, the challenging heterocyclic core of
isatisine prompted us to develop a stereocontrolled method to
access the functionalized tetrahydrofuran, which can be
subsequently converted to the isatisine core by straightforward
transformations.
RESULTS/DISCUSSION
■
Strategy and Methodology Development. Our interest
in isatisine originated from its unique tetracyclic ring system,
which bears a highly oxygenated tetrahydrofuran. As illustrated
in Scheme 1, our synthetic analysis of this alkaloid revealed
During the course of a search of methods for tetrahydrofuran
synthesis, a Mukaiyama-type [3 + 2]-cycloaddition of a
carbamoyl enol ether with an aldehyde reported by Hoppe4j−m
particularly attracted our interest in these possibilities: (1)
cyclization is initiated by formation of an oxocarbenium
between the homoallylic hydroxyl group and an aldehyde
under acidic conditions; (2) the stereochemical course was
dictated by the configuration of the allylic stereocenter. Taking
advantage of these points, we envisioned that alkoxy-substituted
allylsilane 5 bearing allylic C-centered chirality could direct the
stereochemical course of a Mukaiyama-type annulation to
provide a properly functionalized tetrahydrofruan 6 with useful
diastereoselectivity (Scheme 1).5
Scheme 1. Synthetic Strategy and Methodology
Development for Synthesis of (+)-Isatisine A (1)
The development of the [3 + 2]-annulation was initiated
with the preparation of the allylsilane nucleophiles anti-5 and
syn-5, starting from the known epoxysilanes6 cis-7 and trans-7,
respectively (Scheme 2). The annulation substrate anti-5 was
synthesized through epoxide opening reaction of cis-7 with
ethoxy ethynyllithium anion to afford a propargyl silane anti-8
and subsequent Lindlar reduction of the alkyne to the (Z)-
olefin.7 Although an epimerization of the secondary hydroxyl
group in anti-8, which arises from the stabilizing effect of a
cation by the β-silicon effect, is mechanistically possible, any
sign of the epimerization was not observed under the given
reaction conditions. Additionally, a prefect level of regiose-
lectivity in the epoxide opening reaction can be explained by
bond length difference between C−Si and C−C bond. Si−C
bond is ∼1.2 times longer than a normal C−C bond, which
may support the highly regioselective attack of a nucleophile at
the α-carbon from the silicon group.
In a similar manner, syn-5 was also prepared through
nucleophilic epoxide opening of trans-7 and subsequent
reduction of the resulting intermediate propargylic silane syn-
8. However, epoxide trans-7 was unreactive under the same
conditions used for the epoxide opening reaction of cis-7. This
problem was circumvented by the utilization of an AlMe3−BF3·
OEt2 mixture to generate the more nucleophilic ethynyl
aluminum “ate complex” toward an epoxide opening.8
three crucial transformations required to construct the indole
branch and tetracyclic scaffold, including formation of an aryl
C−N bond and densely functionalized tetrahydrofuran. There-
fore, our strategy set out the preparation of the tetrahydrofuran
core as a starting point.
With the availability of reagents anti- and syn-5, the proposed
[3 + 2]-annulation of anti-5 with 2-bromocinnamyl aldehyde
9a9 was carried to furnish tetrahydrofuran 6a, which accounts
Due to the abundance of natural products and bioactive
molecules1,3 bearing a tetrahydrofuran core, methods for the
preparation of functionalized tetrahydrofurans have been
Scheme 2. Preparation of Allylsilanes anti-5 and syn-5
B
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for all of the required carbons of the tetracyclic framework of
isatisine. Guided by Hoppe’s previous results,4e the annulation
was promoted with BF3·OEt2 in CH2Cl2 at −50 °C (Table 1,
Table 2. Mukaiyama-Type [3 + 2]-Annulation of anti-5 with
Aldehydes 9b−i
a b
,
Table 1. Reaction Optimization of the Mukaiyama-Type [3 +
2]-Annulation of anti-5 and 9a
a
b
c
entry
acids (equiv)
temp (°C)
dr
yield (%)
1
2
3
4
5
6
7
BF3·OEt2 (2.0)
Sc(OTf)3 (0.5)
ln(OTf)3 (0.5)
TCA (1.0)
−50
0 to rt
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
67
58
30
53
57
57
87
0
0
0
0
0
TFA (1.0)
CSA (1.0)
PTSA (1.0)
a
The reactions were conducted in a 0.3 M solution of ethoxyl allyl
b
silane anti-5 in CH2Cl2. Diastereoselectivities (dr) were determined
by H NMR. Purification yield after SiO2 column chromatography.
c
1
a
Reactions were carried at a 0.3 M concentration, and 2.0 equiv of
b
aldehyde and 1.0 equiv of acid were employed. Diastereoselectivities
(dr) were determined by H NMR.
1
entry 1), which provided the desired trans,trans,cis-tetrahy-
drofuran 6a in moderate yield albeit with excellent diaster-
eoselectivity (>20:1).2b Similarly, a series of evaluations
utilizing other Lewis acids, such as In(OTf)3 and Sc(OTf)3,
afforded 6a in moderate yields (entries 2 and 3). The series of
reactions using Brønsted acids, such as trichloroacetic acid
(TCA), trifluoroacetic acid (TFA), and camphorsulfonic acid
(CSA), also provided the tetrahydrofuran 6a in moderate yield.
The optimal conditions were found utilizing 1.0 equiv of PTSA
at 0 °C, which afforded the desired product in 87% with a high
level of diastereoselectivity and within a short reaction time (ca.
10 min). As expected, the observed relative stereochemistry of
6a suggested that the annulation proceeded through an
envelope-like transition state (Scheme 1, TS1), where a bulky
silane group is positioned at the pseudoequatorial orientation
and the enol ether is oriented in such a way as to minimize any
developing A1,3-allylic strain between the trialkysilane and
ethoxy group.
Having established optimal reaction conditions, a range of
aldehydes was evaluated to explore the scope of the [3 + 2]-
annulation with anti-5. In that regard, we have learned that
aliphatic aldehydes 9b−e were excellent reaction partners in the
annulations to afford the trans,trans,cis-tetrahydrofurans 6b−e
in high yields and diastereoselectivities (Table 2). Additionally,
various aromatic aldehydes 9f−i, bearing an electron-donating
or -withdrawing substituent, were compatible under the defined
reaction conditions affording tetrahydrofurans 6f−i in high
yields and diastereoselectivities. The series of annulations
shown in Table 2 suggested that ethoxy-terminated allylsilane
anti-5 can be an useful reagent for the preparation of a range of
2,4,5-cis,cis-tetrahydrofurans.
promoter gave superior results in terms of reaction efficiency
(up to 96% yield, 20:1 dr) compared to those using PTSA, and
the expected cis,trans,cis-tetrahydrofurans 10b−i were produced
as the major diastereomer (Table 3). The reactions employing
aliphatic aldehydes 9b−e provided the desired product 10b−e
with attenuating diastereoselectivities regardless of the presence
of α-substitutents. However, cyclopropanecarboxylic aldehyde
9d and aromatic aldehydes 9f−i gave comparable results to the
examples of anti-5, which imply a presumable π-bond
interaction between the enol ether and aryl group to form a
more stable transition state (TS 2). In fact, it has been
documented that the C−C bond of cyclopropane has
significantly more π-bond character than a simple sp3 C−C
bond, since the ring strain in a cyclopropane distorts the
bonding orbital forming a 104° angle.10 The observed
preservation of diastereoselectivity in the case of cyclo-
propanecarboxaldehyde 9d also supports a possible TS
stabilization arising from a π-bond interaction in the transition
state.
Total Synthesis of (+)-Isatisine A: First-Generation
Approach toward the Total Synthesis of (+)-Isatisine A.
Having an established synthesis of tetrahydrofuran 6a, which
bears the required stereochemical relationships and carbon
atoms for the fused-cyclic framework (C2−C14) of the natural
product, our remaining strategy relied on a series of oxidations
to furnish the correct oxidation states required for (+)-isatisine.
Therefore, our initial retrosynthetic analysis began with
disconnection of C7a−N1 to afford an intermediate secondary
amide 11. Further disconnection at the indole side chain C2−
C3′ led to an indole and key intermediate lactam 12, which
would be furnished through a series of oxidations of the
intermediate tetrahydrofuran 6a (Scheme 3).
In studies designed to expand the scope of the tetrahy-
drofuran annulation, allylsilane syn-5 was employed with the
same set of aldehydes 9b−i to gain access to the diastereomeric
tetrahydrofurans. In these experiments, the use of MeSO3H as a
C
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Table 3. Mukaiyama-Type [3 + 2]-Annulation of syn-5 with
Aldehydes 9b−i
Scheme 4. Preparation of Hydroxy Lactam 12
a b
,
To introduce the indole moiety at the C2 position, a direct
addition to lactam 12 was attempted under Lewis acidic
conditions (Scheme 5).13 Fortunately, the utilization of
In(OTf)3 (4.0 equiv) successfully achieved stereoselective
addition to provide α-adduct 11, which was generated by
delivering indole from the less hindered convex face of the
bicyclic intermediate 12 (TS3), without formation of the
undesired β-adduct. Construction of the tetracyclic framework
a
Reactions were carried at 0.3 M concentration, and 2.0 equiv of
b
aldehyde and 1.0 equiv of acid were used. Diastereoselectivities (dr)
were determined by H NMR.
1
Scheme 3. Retrosynthetic Analysis of (+)-Isatisine A (1)
Scheme 5. Construction of 9-H-13-Silylisatisine A (15)
As such, our efforts toward the synthesis of (+)-isatisine were
initiated with an oxidation of tetrahydrofuran 6a to an
intermediate carboxylic acid under Pinnick oxidation conditions
(Scheme 4). In order to introduce the N1 nitrogen atom in the
tetracyclic framework, the carboxylic acid was converted to
amide 13 through the intermediate mixed anhydride.11
Dihydroxylation of the trans-disubstituted double bond in 13
afforded the diol 14 as a mixture of diastereomers (dr = 2:1) in
73% yield, which was subjected to another oxidation in the
presence of TEMPO to produce the desired cyclic aminal 12 as
a 6:1 mixture of diastereomers.12
D
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of isatisine was conducted under modified amidation
conditions,11 originally developed by Buchwald.14 Upon
exposure of 11 to the modified Cu(I)-mediated amidation
conditions, previously used in our syntheses of macrocyclic
lactam natural products, the tetracyclic intermediate 15 was
successfully generated in 80% yield.
stage of the synthesis could serve as an alternative route for the
oxidation at C9 and C13 positions (Scheme 6).
Our revised synthesis began with the oxidation of
tetrahydrofuran 6a to the dihydrofuran 18 (Scheme 7). On
Scheme 7. Preparation of Intermediate 22
At this stage of the synthesis, a series of oxidations at C9 and
C13 to a diol were necessary to complete the total synthesis.
Unfortunately, initial attempts to convert the dimethylphenyl-
silyl group of 15 into a hydroxyl group under Tamao−Fleming
oxidation conditions15 were unsuccessful and only produced
unidentifiable byproducts. With considerable effort, a series of
oxidations at C9 to give α-hydroxyl amide 17 was investigated
under conventional α-hydroxylation conditions16 employing
hindered, non-nucleophilic bases such as LDA, lithium
diethylamide, and KHMDS, with or without the protection of
the indole nitrogen, but surprisingly, intermediate 15 was
completely unreactive under those conditions.
While intermediate 15 was efficiently accessed from
tetrahydrofuran 6a with a minimized number of protection−
deprotection steps, further transformations of 15 to the natural
product under oxidative conditions turned out to be problem-
atic and eventually untenable. Considering these difficulties in
the late-stage oxidation at C9 and C13, an alternative approach
was devised to synthesize (+)-isatisine A.
Second-Generation Approach toward the Total Syn-
thesis of (+)-Isatisine A. Our modified approach shown in
Scheme 6 relied on an early-stage oxidation of tetrahydrofuran
that account, selective α-bromination of aldehyde 6a in the
presence of the styrene-like olefin was conducted using
phenyltrimethylammoniumtribromide (PTAB), which was
directly treated with TBAF at 0 °C to form an intermediate
unsaturated aldehyde.18 Due to the instability of the aldehyde,
it was immediately subjected to the venerable Corey−Ganem
oxidation using MnO2 in the presence of NaCN to directly
afford the unsaturated methyl ester 18 in 57% yield from
tetrahydrofuran 6a.19
Scheme 6. Revised Strategy for (+)-Isatisine A
Initially, we planned a stepwise dihydroxylation−protection
sequence to secure the formation of the key intermediate
hydroxyl lactam 19. In this approach, the more nucleophilic
styrene-like olefin in 18 chemoselectively underwent dihydrox-
ylation using 1.0 equiv of NMO to furnish diol 20 as a 1.5:1
mixture of diastereomers. Protection of the mixture of diols as a
cyclic carbonate and subsequent dihydroxylation of the
unsaturated ester in 21 provided an intermediate diol with a
perfect level of selectivity favoring the α-face, which was
followed by an acetonide formation to produce oxolane 22 in
67% yield (three steps) from diol 20. At this stage, the relative
configuration of the diol was assigned by NOE measurements
of 22 after separation and purification of the individual
diastereomers.2b
Removal of the carbonate protecting group in 22 under basic
(hydrolysis) conditions also resulted in the cleavage of the
methyl ester to form the intermediate dihydroxy acid 23, which
underwent spontaneous lactonization to give the bicyclic
lactone 24 (Scheme 8). Treatment of this material with a
solution of anhydrous NH3 in MeOH provided intermediate
amide 25, which was subjected to oxidation with TEMPO and
NaOCl at room temperature.12 As anticipated, the oxidation of
the dihydroxy amide 25 resulted in a spontaneous cyclization to
afford the key advanced intermediate hydroxyl lactam 19, which
possessed the required oxidation states to be converted to the
natural product.
6a to intermediate hydroxyl lactam 19, which also established
the required oxidation states present in the natural product. In
the course of [3 + 2]-annulation, as we anticipated, the
configuration of the dimethylphenyl silane group proved to be a
crucial stereocontrol element, which successfully transferred its
C-centered chirality to the product tetrahydrofuran with a high
level of selectivity (dr ≥20:1). However, our previous attempts
revealed that direct oxidation of the silicon group to a hydroxyl
group was ineffective under the typically reliable Tamao−
Fleming conditions.15 Meanwhile, a trialkylsilicon group is also
known to undergo elimination arising from its σ-donating
character to afford an olefin when a leaving group is on the
adjacent carbon.17 Thus, elimination of the silicon group and
subsequent dihydroxylation of the resulting olefin at the early
The intermediate hydroxyl lactam can also be prepared
through a four-step reaction sequence from diene 18 with an
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icity of the oxygen atoms by a complicated hydrogen-bonding
network between the hydroxyl groups.
Scheme 8. Preparation of Hydroxy Lactam 19
Accordingly, we attempted a cascade-like protection and
lactonization sequence as an alternative pathway to lactone 24
(Scheme 9). In this approach, we presumed that isopropylidene
formation is a completely reversible process and forms the
thermodynamically more stable lactone 24 rather than bis-
acetonide 27. In order to validate this hypothesis, the
dihydrofuran 18 was converted to the intermediate carboxylic
acid 26, which was directly treated with 2,2-dimethoxypropane
(2,2-DMP) under reflux conditions. Fortunately, the reaction
sequence furnished the desired lactone 24 as a mixture of
diastereomers at C2 and C3 without detectable formation of
bis-acetonide 27. For experimental simplification, the resulting
mixture of diastereomeric lactones was directly subjected to
aminolysis and subsequent TEMPO oxidation without
purification to afford spectroscopically clean 19 in 20% yield
as a single diastereomer.20
With access to intermediate hydroxyl lactam 19, we turned
our attention to the stereoselective incorporation of the
branching indole nucleus.13 Surprisingly, in this case, 19 was
revealed to be totally unreactive under the previously reported
reaction conditions [4.0 equiv of In(OTf)3] (Scheme 10). After
Scheme 10. Completion of the Total Synthesis of
(+)-Isatisine A (1)
equal level of efficiency (Scheme 9). Both the styrene-like olefin
and unsaturated ester were concomitantly dihydroxylated by
Scheme 9. Alternative Route to Hydroxyl Lactam 19
extensive screening of reaction conditions, we learned that
treatment of 19 with TFAA (1.2 equiv) and pyridine at 0 °C
readily activated the hydroxyl lactam to an intermediate acyl
iminium ion, and subsequent addition of a solution of the
indole (5.0 equiv) in CH2Cl2 produced the desired adduct 28
in 82% yield as a single diastereomer. The stereochemistry and
absolute configuration of the indole branched quaternary
carbon center of 28 was confirmed by single-crystal X-ray
crystallographic analysis.2b
At the final stage of this synthesis, the assembly of the fused
tetracyclic framework was carried out by employing a
copper(I)-mediated intramolecular amidation under the
conditions that were used in our first-generation synthesis.11
As anticipated, the advanced tetracyclic intermediate 29 was
successfully generated through Cu(I)-mediated coupling in
90% yield. Subsequent cleavage of the methyl ether5b,21 and
acetonide with an excess amount of 1.0 M solution of BBr3 in
CH2Cl2 in the presence of 15-crown-5 and NaI (3.0 equiv)
successfully provided (+)-isatisine A (1) in 80% yield.
catalytic OsO4 using an excess amount of NMO, which was
subsequently treated with 1.0 N solution of NaOH to produce
intermediate tetraol 26 as a mixture of diastereomers (dr =
3:2−6:1) arising from the benzylic 1,2-diol. Interestingly, this
tetraol was totally inactive under conditions intended to
produce a lactone, possibly due to the attenuating nucleophil-
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mg). The air in the reaction vessel was substituted with H2 gas
employing vacuum (three times) and stirring was continued for 1 h.
The mixture was then filtered through a pad of Celite, and the solution
was concentrated under reduced pressure to give a yellow residue.
Purification over silica gel with hexanes/ethyl acetate (10/1) afforded
anti-5 as a colorless oil (2.0 g, 80%, two steps): [α]D20 = −34.2 (c 1.0,
CONCLUSION
■
We have developed a silicon-directed Mukaiyama-type [3 + 2]-
annulation to construct highly functionalized tetrahydrofurans.
This reaction displayed remarkable compatibility with a several
types of aromatic and aliphatic aldehydes and provided an
access to a wide range of functionalized tetrahydrofurans with
considerable structural and stereochemical variation. A total
synthesis of (+)-isatisine A (1) has been achieved starting from
the highly functionalized tetrahydrofuran 6a, which was
generated through this silicon-directed Mukaiyama-type [3 +
2]-annulation. Additionally, this synthesis represents another
application of a Buchwald-type amidation culminating the
assembly of the 3-indolone moiety of the complex natural
product. Further studies to synthesize naturally occurring
materials, which bear a complex tetrahydrofuran core, employ-
ing this annulation methodology are in progress and may be
reported at a later time.
1
CHCl3); H NMR (CDCl3, 500 MHz) δ 7.57−7.55 (m, 2H), 7.32−
7.29 (m, 3H), 5.99 (d, J = 6.5, 1H), 4.42 (dd, J = 11.0, 5.2 Hz, 1H),
3.85 (m, 1H), 3.66 (qd, J = 7.2, 6.8 Hz, 2H), 3.28−3.20 (m, 2H), 3.25
(s, 3H), 2.36 (dd, J = 3.5, 1.0 Hz, 1H), 2.30 (dd, J = 10.5, 3.5 Hz, 1H),
1.15 (t, J = 7.0 Hz, 3H), 0.34 (s, 3H), 0.30 (s, 3H); 13C NMR (CDCl3,
75 MHz) δ 144.3, 138.4, 134.0, 128.7, 127.4, 101.9, 77.0, 69.9, 67.2,
58.6, 28.4, 15.1, −3.5, −3.9; IR (film) νmax 3465, 2976, 2895, 1652,
1427, 1251 cm−1; HRMS (CI, NH3) m/z [M + Na]+ calcd for
C16H26NaO3Si 317.1549, found 317.1577.
(2S,3S,Z)-3-(Dimethyl(phenyl)silyl)-5-ethoxy-1-methoxypent-4-
en-2-ol (syn-5). A solution of ethoxy acetylene (40 wt % in hexane, 3.2
mL, 13.5 mmol) in diethyl ether (25 mL) was cooled to −78 °C under
an atmosphere of Ar. n-BuLi (2.5 M in hexane, 5.4 mL, 13.5 mmol)
was added dropwise, and stirring was continued at −78 °C for 1 h. A
2.0 M solution of Me3Al in heptane (6.75 mL, 13.5 mmol) and a
solution of trans-76a (1.5 g, 6.75 mmol) in ethyl ether (9 mL) were
successively added, which was followed by BF3·OEt2 (1.7 mL, 13.5
mmol). After 30 min at −78 °C, satd NaHCO3 (34 mL) was added,
and the mixture was diluted with ethyl acetate (50 mL). The resulting
layers were separated, and the organic layer were dried over
magnesium sulfate, filtered, and concentrated in vacuo to obtain a
yellowish residue. Column chromatography over silica gel with
hexanes/ethyl acetate (10/1) afforded syn-8 as a yellowish oil (1.67
g, 85%): [α]D20 = −45.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
δ 7.65−7.63 (m, 2H), 7.37−7.34 (m, 3H), 3.95 (q, J = 6.8 Hz, 2H),
3.79−3.73 (m, 1H), 3.57 (dd, J = 9.6, 2.8 Hz, 1H), 3.38 (dd, J = 9.6,
7.6 Hz, 1H), 3.33 (s, 3H), 2.55 (d, J = 4.8 Hz, 1H), 2.11 (d, J = 8.8 Hz,
1H), 1.29 (t, J = 6.8 Hz, 3H), 0.47 (s, 3H), 0.46 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 137.5, 134.0, 128.9, 127.4, 92.2, 76.4, 58.7, 35.3,
22.3, 14.2, −3.2, −3.3; IR (film) νmax 3453, 2896, 2258, 1427, 1247
cm−1.
EXPERIMENTAL SECTION
■
General Experimental Procedures. All reactions were carried
out in oven or flame-dried glassware under argon atmosphere.
Triethylamine and 2,6-lutidine were distilled and stored over
potassium hydroxide. n-Butyllithium was purchased and standardized
by titration with menthol/2,2′-dipyridyl. All other reagents were used
as supplied. Dichloromethane, toluene, diethyl ether, benzene,
tetrahydrofuran, and acetonitrile were obtained from an anhydrous
solvent system (alumina) and used without further drying. Unless
otherwise noted, reactions were magnetically stirred and monitored by
thin-layer chromatography with 0.20 mm silica gel 60 Å plates. Flash
chromatography was performed on 32−63 μm 60 Å silica gel. Yields
refer to chromatographically and spectroscopically pure compounds,
unless otherwise noted. 1H NMR spectra were taken in CDCl3,
methanol-d4, and CD3CN at 400 or 500 MHz (as indicated),
respectively. 13C NMR spectra were also taken in CDCl3, methanol-d4,
and CD3CN at 100 or 125 MHz (as indicated), respectively. Chemical
shifts are reported in parts per million relative to CDCl3 (1H, δ 7.24;
13C, δ 77.0), methanol-d6 (1H, δ 3.31; 13C, δ 49.0), and acetonitrile-d3
(1H, δ 1.94; 13C, δ 118.7). Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, sept =
septuplet m = multiplet, br = broad, obsc = obscured), coupling
A solution of syn-8 (1.57g, 5.37 mmol) and pyridine (0.9 mL, 10.7
mmol) in ethyl acetate (50 mL) was treated with Lindlar’s catalyst
(157 mg). The air in the reaction vessel was substituted with H2 gas
through a vacuum-H2 reload process (three times), and stirring was
continued for 6 h. The mixture was then filtered through a pad of
Celite, and the solution was concentrated under reduced pressure to
1
give a yellow residue. Purification over silica gel with hexanes/ethyl
constant, integration. Diastereomeric ratios were determined by H
20
acetate (10/1) afforded syn-5 as a colorless oil (1.45 g, 92%): [α]D
=
NMR (500 MHz) analysis of crude mixtures, operating at signal/noise
ratio of 200:1. Infrared resonance spectra were recorded as a thin film
on KBr plate. High-resolution mass spectra (HRMS) were obtained by
electrospray ionization using a Q-TOF mass spectrometer in positive-
ion mode (M + H or M + Na) as indicated.
−32.6 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.57−7.55 (m,
2H), 7.31−7.29 (m, 3H), 5.91 (d, J = 6.5 Hz, 1H), 4.10 (dd, J = 11.0,
6.0 Hz, 1H), 3.75−3.71 (m, 1H), 3.70 (q, J = 7.0 Hz, 1H), 3.64 (q, J =
6.5 Hz, 1H), 3.15 (t, J = 9.0 Hz, 1H), 2.44 (dd, J = 11.0, 9.0 Hz, 1H),
2.32 (d, J = 3.5 Hz, 1H), 1.16 (t, J = 7.0 Hz, 3H), 0.35 (s, 3H), 0.32 (s,
3H); 13C NMR (CDCl3, 75 MHz): 144.4, 135.5, 134.0, 128.5, 127.2,
103.3, 76.9, 71.9, 67.2, 58.6, 29.3, 15.1, −2.8, −3.3; IR (film) νmax
3461, 2977, 2894, 1653, 1245 cm−1; HRMS (CI, NH3) m/z [M +
Na]+ calcd for C16H26NaO3Si 317.1549, found 317.1579.
(2S,3R,Z)-3-(Dimethyl(phenyl)silyl)-5-ethoxy-1-methoxypent-4-
en-2-ol (anti-5). A solution of ethoxy acetylene (50 wt % in hexane,
2.5 mL, 12.8 mmol) in diethyl ether (60 mL) was cooled to −78 °C
under an atmosphere of Ar. n-BuLi (2.5 M in hexane, 5.1 mL, 12.8
mmol) was added dropwise for 5 min at −78 °C, and stirring was
continued for 1 h at the same temperature. A solution of cis-76a (1.91
g, 6.75 mmol) in ethyl ether (20 mL) and BF3·OEt2 (1.7 mL, 13.5
mmol) were successively added, and the reaction mixture was stirred
for 30 min at −78 °C before addition of satd NaHCO3 (80 mL). Ethyl
acetate (80 mL) was added, and the resulting layers were separated.
The organic layer was dried over magnesium sulfate, filtered, and
concentrated in vacuo to obtain a yellowish residue. Purification over
silica gel with hexanes/ethyl acetate (10/1) afforded an inseparable
mixture of anti-8 and unidentified byproduct (2.25 g): 1H NMR
(CDCl3, 500 MHz) δ 7.58−7.56 (m, 2H), 7.35−7.31 (m, 3H), 4.00
(q, J = 7.0 Hz, 2H), 3.73 (m, 1H), 3.38 (dd, J = 9.5, 7.0 Hz, 1H), 3.30
(dd, J = 9.5, 5.0 Hz, 1H), 3.27 (s, 3H), 2.07 (d, J = 3.0 Hz, 1H), 2.02
(d, J = 7.0 Hz, 1H), 1.30 (t, J = 7.5 Hz, 3H), 0.42 (s, 3H), 0.41 (s,
3H).
General Procedure for the Silicon-Directed Mukaiyama-
Type [3 + 2]-Annulation of anti-5. Ethoxy allyl silane ( )-anti-5
(40 mg, 0.136 mmol) and aldehyde 9 (0.271 mmol) were dissolved
with methylene chloride (0.45 mL) in a round-bottom flask. The
mixture was cooled to 0 °C, and PTSA monohydrate (26 mg, 0.136
mmol) was added in one portion. The solution was allowed to stir for
10 min at 0 °C before addition of satd NaHCO3 solution (1.0 mL).
The mixture was diluted with methylene chloride (3.0 mL), and the
resulting layers were separated. The organic layer was dried over
magnesium sulfate, filtered, and concentrated in vacuo to obtain a
crude product. Purification over silica gel with hexanes/ethyl acetate
(20/1 to 10/1) provided product tetrahydrofuran 6:
(
)-(2R,3R,4R,5S)-2-Butyl-4-(dimethyl(phenyl)silyl)-5-
(methoxymethyl)tetrahydrofuran-3-carbaldehyde (6b). Aldehyde
9b (29 μL, 0.271 mmol) was used following the general procedure.
Tetrahydrofuran 6b was obtained as a colorless oil (40 mg, 88% yield):
To a solution of anti-8 (2.25g, 7.69 mmol) and pyridine (1.3 mL,
15.4 mmol) in ethyl acetate (50 mL) was added Lindlar’s catalyst (157
G
DOI: 10.1021/acs.joc.5b00051
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
1
1H NMR (CDCl3, 500 MHz) δ 9.52 (d, J = 5.0 Hz, 1H), 7.47−7.45
drofuran 6g was obtained as a colorless oil (42 mg, 84% yield): H
NMR (CDCl3, 500 MHz) δ 9.01 (dd, J = 3.8, 0.7 Hz, 1H), 7.55−7.49
(m, 2H), 7.42−7.33 (m, 3H), 7.15 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0
Hz, 2H), 4.82 (d, J = 7.4 Hz, 1H), 4.16−4.09 (m, 1H), 3.42−3.37 (m,
2H), 3.33 (s, 2H), 3.04 (dtd, J = 7.4, 3.8, 1.9 Hz, 1H), 2.28 (s, 3H),
1.93 (ddd, J = 9.5, 5.9, 1.0 Hz, 1H), 0.38 (d, J = 10.5 Hz, 6H); 13C
NMR (CDCl3, 125 MHz) δ 201.0, 137.4, 135.9, 133.9, 133.6, 129.7,
129.1, 128.1, 125.9, 82.1, 81.0, 74.7, 59.3, 58.1, 28.0, 21.1, −4.0, −4.7;
IR (film) νmax 3047, 1715, 1515, 1455, 1252 cm−1; HRMS (CI, NH3)
m/z [M + Na]+ calcd for C22H28NaO3Si 391.1705, found 391.1700.
( )-(2S,3R,4R,5S)-4-(Dimethyl(phenyl)silyl)-5-(methoxymethyl)-2-
(2 methoxyphenyl)tetrahydrofuran-3-carbaldehyde (6h). Aldehyde
9h (37 mg, 0.271 mmol) was used following the general procedure.
Tetrahydrofuran 6h was obtained as a colorless oil (37 mg, 71% yield):
1H NMR (CDCl3, 500 MHz) δ 9.00 (d, J = 3.5 Hz, 1H), 7.57−7.51
(m, 2H), 7.49 (ddd, J = 7.7, 1.8, 0.9 Hz, 1H), 7.42−7.35 (m, 3H),
7.23−7.14 (m, 1H), 6.94−6.85 (m, 1H), 6.79 (dd, J = 8.2, 1.0 Hz,
1H), 5.03 (dd, J = 7.1, 0.9 Hz, 1H), 4.11 (ddd, J = 9.5, 5.7, 3.1 Hz,
1H), 3.79 (s, 3H), 3.43−3.34 (m, 2H), 3.32 (s, 3H), 3.30−3.22 (m,
2H), 1.86 (dd, J = 9.5, 5.9 Hz, 1H), 0.39 (d, J = 16.9 Hz, 6H); 13C
NMR (CDCl3, 125 MHz) δ 201.1, 155.3, 136.2, 133.9, 129.6, 128.5,
128.0, 126.4, 125.3, 120.5, 109.7, 80.5, 77.6, 74.9, 59.3, 55.7, 55.2, 27.9,
−3.9, −4.7; IR (film) νmax 2979, 2837, 1719, 1602, 1491, 1246 cm−1;
HRMS (CI, NH3) m/z [M + Na]+ calcd for C22H28NaO4Si 407.1655,
found 407.1661.
(m, 2H), 7.37−7.32 (m, 3H), 3.96 (ddd, J = 9.0, 6.5, 2.5 Hz, 1H), 3.60
(ddd, J = 8.0, 6.0, 6.0 Hz, 1H), 3.27−3.19 (m, 2H), 3.25 (s, 3H), 2.68
(ddd, J = 6.0, 4.5, 4.5 Hz, 1H), 2.68 (ddd, J = 6.0, 4.5, 4.5 Hz, 1H),
1.67 (dd, J = 9.0, 4.5 Hz, 1H), 1.65−1.60 (m, 1H), 1.54−1.47 (m,
1H), 1.40−1.33 (m, 1H), 1.25−1.20 (m, 3H), 0.82 (t, J = 7.0 Hz, 3H),
0.33 (s, 3H), 0.32 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 201.8,
135.9, 133.7, 129.6, 128.0, 82.0, 80.3, 74.7, 59.2, 56.3, 30.3, 28.6, 28.0,
22.4, 13.7, −4.1, −4.7; IR (film) νmax 3069, 2955, 1718, 1427, 1252,
1114 cm−1; HRMS (CI, NH3) m/z [M + Na]+ calcd for
C19H30NaO3Si 357.1862, found 357.1852.
( )-(2R,3R,4R,5S)-4-(Dimethyl(phenyl)silyl)-2-isopropyl-5-
(methoxymethyl)tetrahydrofuran-3-carbaldehyde (6c). Aldehyde 9c
(25 μL, 0.271 mmol) was used following the general procedure.
Tetrahydrofuran 6c was obtained as a colorless oil (38 mg, 87% yield):
1H NMR (CDCl3, 500 MHz) δ 9.53 (d, J = 5.4 Hz, 1H), 7.52−7.42
(m, 2H), 7.42−7.27 (m, 3H), 3.95 (ddd, J = 8.5, 6.0, 2.4 Hz, 1H), 3.28
(dd, J = 10.7, 2.4 Hz, 1H), 3.26 (s, 3H), 3.19 (dd, J = 10.7, 6.0 Hz,
1H), 3.11 (dd, J = 10.3, 5.5 Hz, 1H), 2.69 (td, J = 5.4, 3.5 Hz, 1H),
1.84 (dp, J = 10.3, 6.5 Hz, 1H), 1.61 (dd, J = 8.6, 3.5 Hz, 1H), 0.97 (d,
J = 6.4 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H), 0.34 (d, J = 7.7 Hz, 6H); 13C
NMR (CDCl3, 125 MHz) δ 206.2, 138.6, 132.8, 93.3, 85.1, 81.8, 79.4,
64.1, 60.2, 33.8, 33.1, 25.9, 23.3, 0.6, 0.0; IR (film) νmax 3049, 2875,
1716, 1470, 1252 cm−1; HRMS (CI, NH3) m/z [M + Na]+ calcd for
C18H28NaO3Si 343.1705, found 343.1708.
( )-(2R,3R,4R,5S)-2-Cyclopropyl-4-(dimethyl(phenyl)silyl)-5-
(methoxymethyl)tetrahydrofuran-3-carbaldehyde (6d). Aldehyde
9d (20 μL, 0.271 mmol) was used following the general procedure.
Tetrahydrofuran 6d was obtained as a colorless oil (37 mg, 85% yield):
1H NMR (CDCl3, 500 MHz) δ 9.70 (dd, J = 3.9, 0.6 Hz, 1H), 7.50−
7.39 (m, 2H), 7.41−7.26 (m, 3H), 3.92 (dddd, J = 9.5, 6.1, 2.8, 0.6 Hz,
1H), 3.27−3.23 (m, 5H), 0.31−0.29 (m, 4H), 3.02 (dd, J = 9.1, 7.1
Hz, 1H), 1.84 (ddd, J = 9.5, 6.4, 0.6 Hz, 1H), 0.32−0.29 (m, 7H), 2.82
(dddd, J = 7.0, 6.3, 3.9, 0.6 Hz, 1H), 0.91−0.82 (m, 1H), 0.63−0.54
(m, 1H), 0.48 (ddd, J = 9.2, 8.4, 5.5 Hz, 1H), 0.39−0.32 (m, 2H),
0.38−0.32 (m, 2H), 0.32 (s, 3H), 0.30 (s, 3H), 0.17−0.10 (m, 1H);
13C NMR (CDCl3, 125 MHz) δ 201.5, 136.0, 133.8, 129.6, 128.0, 86.1,
80.7, 74.8, 59.2, 57.2, 27.7, 11.2, 5.3, 1.8, −4.1, −4.7; IR (film) νmax
3048, 2884, 1718, 1456, 1252 cm−1; HRMS (CI, NH3) m/z [M +
Na]+ calcd for C18H26NaO3Si 341.1549, found 341.1538.
( )-(2R,3R,4R,5S)-2-Cyclohexyl-4-(dimethyl(phenyl)silyl)-5-
(methoxymethyl)tetrahydrofuran-3-carbaldehyde (6e). Aldehyde 9e
(33 μL, 0.271 mmol) was used following the general procedure.
Tetrahydrofuran 6e was obtained as a colorless oil (40 mg, 82% yield):
1H NMR (CDCl3, 500 MHz) δ 9.53 (d, J = 5.4 Hz, 1H), 7.50−7.43
(m, 2H), 7.40−7.30 (m, 3H), 3.93 (ddd, J = 8.5, 6.0, 2.5 Hz, 1H), 3.28
(dd, J = 10.7, 2.5 Hz, 1H), 3.26 (s, 1H), 3.18 (ddd, J = 10.1, 9.2, 5.7
Hz, 3H), 2.69 (td, J = 5.4, 3.4 Hz, 1H), 2.06−1.94 (m, 1H), 1.64−1.52
(m, 7H), 1.23−1.00 (m, 4H), 0.93−0.74 (m, 2H), 0.34 (d, J = 7.0 Hz,
6H); 13C NMR (CDCl3, 125 MHz) δ 201.4, 136.0, 133.8, 129.6,
128.0, 87.0, 80.0, 74.6, 59.3, 55.0, 38.2, 31.3, 28.6, 28.1, 26.1, 25.4,
25.2, −4.2, −4.8; IR (film) νmax 2924, 2851, 1716, 1450, 1252 cm−1;
HRMS (CI, NH3) m/z [M + Na]+ calcd for C21H32NaO3Si 383.2018,
found 383.2010.
( )-(2S,3R,4R,5S)-2-(4-Bromophenyl)-4-(dimethyl(phenyl)silyl)-5-
(methoxymethyl)tetrahydrofuran-3-carbaldehyde (6i). Aldehyde 9i
(50 mg, 0.271 mmol) was used following the general procedure.
Tetrahydrofuran 6i was obtained as a colorless oil (48 mg, 81% yield):
1H NMR (CDCl3, 500 MHz) δ 8.98 (d, J = 3.9 Hz, 1H), 7.51 (dd, J =
7.4, 1.9 Hz, 2H), 7.45−7.31 (m, 5H), 7.18−7.11 (m, 2H), 4.78 (d, J =
7.4 Hz, 1H), 3.46−3.33 (m, 3H), 4.13 (ddd, J = 9.5, 5.9, 2.5 Hz, 1H),
3.43−3.33 (m, 2H), 3.32 (s, 3H), 1.93 (dd, J = 9.5, 6.0 Hz, 1H), 0.38
(d, J = 9.9 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 200.5, 135.8,
135.7, 133.8, 131.6, 129.8, 128.1, 127.9, 127.7, 121.7, 103.1, 81.4, 81.2,
74.5, 59.3, 58.0, 28.1, −4.0, −4.7; IR (film) νmax 2979, 2884, 1718,
1488, 1399, 1253 cm−1. HRMS (CI, NH3) m/z [M + Na]+ calcd for
C21H25BrNaO3Si 455.0654, found 455.0649.
General Procedure for Silyl-Directed Mukaiyama-Type [3 +
2]-Annulation of syn-5. Ethoxy allyl silane ( )-syn-5 (40 mg, 0.136
mmol) and aldehyde 9 (0.271 mmol) were added into a round-bottom
flask followed by methylene chloride (0.45 mL). The mixture was
cooled to 0 °C, and methansulfonic acid (9.0 μL, 0.136 mmol) was
added in one portion. The reaction was allowed to stir for 10 min at 0
°C before being quenched with satd NaHCO3 solution (1.0 mL).
Upon warming to room temperature, the layers were separated and
the aqueous phase was extracted with methylene chloride (3.0 mL).
The combined organic layers were dried over magnesium sulfate,
filtered, and concentrated in vacuo to obtain a crude product.
Purification over silica gel with hexanes/ethyl acetate (20/1 to 10/1)
afforded a furan 10 as an oil:
( )-(2S, 3S, 4S, 5S)-2-Butyl-4-(dimethyl(phenyl)silyl)-5-
(methoxymethyl)tetrahydrofuran-3-carbaldehyde (10b). Aldehyde
9b (29 μL, 0.271 mmol) was used following the general procedure.
Tetrahydrofuran 10b was obtained as a colorless oil (34 mg, 75%
( )-(2S,3R,4R,5S)-4-(Dimethyl(phenyl)silyl)-5-(methoxymethyl)-2-
phenyltetrahydrofuran-3-carbaldehyde (6f). Aldehyde 9f (28 μL,
0.271 mmol) was used following the general procedure. Tetrahy-
1
yield): H NMR (CDCl3, 500 MHz) δ 9.42 (d, J = 4.5, 1H), 7.48−
7.35 (m, 2H), 7.35−7.30 (m, 3H), 4.43 (ddd, J = 8.0, 6.0, 3.5 Hz, 1H),
4.21 (ddd, J = 9.0, 9.0, 4.5 Hz, 1H), 3.24 (dd, J = 10.0, 3.5 Hz, 1H),
3.18−3.13 (m, 1H), 3.16 (s, 3H), 3.05 (ddd, J = 13.5, 9.0, 4.5 Hz, 1H),
2.21 (dd, J = 9.0, 8.5 Hz, 1H), 1.57−1.49 (m, 1H), 1.45−1.40 (m,
2H), 1.29−1.24 (m, 3H), 0.84 (t, J = 7.5 Hz, 3H), 0.34 (s, 3H), 0.39
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 202.5, 137.3, 133.6, 129.3,
127.9, 80.6, 80.5, 74.0, 58.6, 56.3, 31.4, 30.8, 28.7, 22.6, 13.8, −2.4,
−3.1; IR (film) νmax 3069, 2929, 1719, 1427, 1251, 1111 cm−1; HRMS
(CI, NH3) m/z [M + Na]+ calcd for C19H30NaO3Si 357.1862, found
357.1857.
1
drofuran 6f was obtained as a colorless oil (43 mg, 89% yield): H
NMR (CDCl3, 500 MHz) δ 8.99 (d, J = 3.5 Hz, 1H), 7.54−7.51 (m,
2H), 7.40−7.34 (m, 3H), 7.29−7.19 (m, 5H), 4.83 (d, J = 7.5 Hz,
1H), 4.14 (ddd, J = 9.5, 5.5, 3.5 Hz, 1H), 3.40−3.39 (m, 2H), 3.33 (s,
3H), 3.07 (ddd, J = 7.0, 5.5, 3.5 Hz, 1H), 1.94 (dd, J = 9.5, 6.0 Hz,
1H), 0.39 (s, 3H), 0.37 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
200.8, 136.6, 135.8, 133.8, 129.7, 128.4, 128.0, 127.8, 125.9, 82.1, 81.0,
74.6, 59.2, 58.1, 27.9, −3.9, −4.6; IR (film) νmax 3068, 2878, 1719,
1427, 1252, 1110 cm−1; HRMS (CI, NH3) m/z [M + H]+ calcd for
C21H27O3Si 355.1729, found 355.1727.
( )-(2S,3S,4S,5S)-4-(Dimethyl(phenyl)silyl)-2-isopropyl-5-
(methoxymethyl)tetrahydrofuran-3-carbaldehyde (10c). Aldehyde
9c (25 μL, 0.271 mmol) was used following the general procedure.
Tetrahydrofuran 10c was obtained as a colorless oil (32 mg, 74%
( )-(2S,3R,4R,5S)-4-(Dimethyl(phenyl)silyl)-5-(methoxymethyl)-2-
(p-tolyl)tetrahydrofuran-3-carbaldehyde (6g). Aldehyde 9g (32 μL,
0.271 mmol) was used following the general procedure. Tetrahy-
H
DOI: 10.1021/acs.joc.5b00051
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
1
yield): 1H NMR (CDCl3, 500 MHz) δ 9.52 (dd, J = 5.0, 0.6 Hz, 1H),
7.52−7.42 (m, 2H), 7.38−7.31 (m, 3H), 4.46 (ddd, J = 8.3, 6.3, 3.7
Hz, 1H), 3.73 (dd, J = 9.1, 7.2 Hz, 1H), 3.26 (dd, J = 10.3, 3.7 Hz,
1H), 1.89−1.77 (m, 1H), 3.22−3.18 (m, 1H), 3.18 (s, 3H), 2.97 (td, J
= 7.0, 5.0 Hz, 1H), 2.14 (dd, J = 8.4, 6.9 Hz, 1H), 1.91−1.74 (m, 1H),
0.97 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H), 0.36 (s, 3H), 0.29
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 201.7, 137.5, 133.6, 129.4,
127.9, 86.1, 80.6, 73.9, 58.7, 56.0, 31.0, 29.2, 20.3, 19.3, −2.2, −3.0; IR
(film) νmax 2958, 2890, 1718, 1470, 1389, 1252 cm−1; HRMS (CI,
NH3) m/z [M + Na]+ calcd for C18H28NaO3Si 343.1705, found
343.1704.
mg, 76% yield): H NMR (CDCl3, 500 MHz) δ 8.74 (d, J = 4.7 Hz,
1H), 7.54 (dd, J = 4.8, 2.5 Hz, 2H), 7.50 (dd, J = 7.7, 1.9 Hz, 1H), 7.38
(s, 3H), 7.24 (td, J = 7.8, 1.9 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 6.80 (d,
J = 8.2 Hz, 1H), 5.62 (dd, J = 8.6, 2.4 Hz, 1H), 4.74−4.59 (m, 1H),
3.79 (s, 3H), 3.50−3.42 (m, 1H), 3.36 (dd, J = 10.2, 3.5 Hz, 1H), 3.29
(ddd, J = 10.2, 6.1, 2.0 Hz, 1H), 3.24 (s, 3H), 2.28−2.19 (m, 1H), 0.41
(s, 3H), 0.33 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 201.6, 155.0,
137.2, 133.7, 129.3, 128.5, 127.9, 126.7, 126.6, 120.5, 109.6, 81.6, 76.4,
74.1, 58.8, 56.2, 55.0, 30.5, −2.3, −3.1; IR (film) νmax 2980, 2835,
1720, 1600, 1589, 1284 cm−1; HRMS (CI, NH3) m/z [M + Na]+ calcd
for C22H28NaO4Si 407.1655, found 407.1670.
( )-(2S,3S,4S,5S)-2-Cyclopropyl-4-(dimethyl(phenyl)silyl)-5-
(methoxymethyl)tetrahydrofuran-3-carbaldehyde (10d). Aldehyde
9d (20 μL, 0.271 mmol) was used following the general procedure.
Tetrahydrofuran 10d was obtained as a colorless oil (42 mg, 96%
yield): 1H NMR (CDCl3, 500 MHz) δ 9.57 (d, J = 4.4 Hz, 1H), 7.50−
7.46 (m, 2H), 7.37−7.31 (m, 3H), 4.43 (ddd, J = 7.8, 5.3, 3.5 Hz, 1H),
3.59 (t, J = 8.9 Hz, 1H), 3.25−3.18 (m, 2H), 3.12 (s, 3H), 2.36−2.31
(m, 1H), 0.88 (dddd, J = 12.5, 10.7, 6.1, 2.9 Hz, 1H), 0.66−0.56 (m,
1H), 0.48−0.36 (m, 2H), 0.34 (s, 3H), 0.30 (s, 3H), 0.22−0.13 (m,
1H); 13C NMR (CDCl3, 125 MHz) δ 202.1, 137.3, 133.7, 129.4,
127.9, 85.1, 81.2, 74.5, 58.6, 56.8, 31.1, 12.4, 4.9, 2.1, −2.5, −3.2; IR
(film) νmax 2980, 2828, 1772, 1394, 1251 cm−1; HRMS (CI, NH3) m/z
[M + Na]+ calcd for C18H26NaO3Si 341.1549, found 341.1548.
( )-(2S,3S,4S,5S)-2-Cyclohexyl-4-(dimethyl(phenyl)silyl)-5-
(methoxymethyl)tetrahydrofuran-3-carbaldehyde (10e). Aldehyde
9e (33 μL, 0.271 mmol) was used following the general procedure.
Tetrahydrofuran 10e was obtained as a colorless oil (42 mg, 86%
yield): 1H NMR (CDCl3, 500 MHz) δ 9.52 (dt, J = 5.0, 0.9 Hz, 1H),
7.52−7.43 (m, 2H), 7.37−7.30 (m, 3H), 4.45 (ddd, J = 8.8, 6.4, 3.7
Hz, 1H), 3.77 (dd, J = 8.9, 7.1 Hz, 1H), 3.27−3.22 (m, 1H), 3.21−
3.17 (m, 1H), 3.17 (s, 3H), 2.96 (td, J = 6.9, 5.0 Hz, 1H), 2.11 (ddd, J
= 7.6, 6.5, 1.0 Hz, 1H), 1.95−1.88 (m, 1H), 1.71−1.57 (m, 5H), 1.22−
1.07 (m, 4H), 0.35 (s, 3H), 0.29 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 201.7, 137.5, 133.6, 129.4, 128.0, 85.1, 80.4, 73.8, 58.7, 55.8,
38.7, 30.8, 30.5, 29.6, 26.2, 25.7, 25.5, −2.1, −3.0; IR (film) νmax 2924,
2852, 1718, 1450, 1251, 1110 cm−1; HRMS (CI, NH3) m/z [M +
Na]+ calcd for C21H32NaO3Si 383.2018, found: 383.2042.
( )-(2R,3S,4S,5S)-2-(4-Bromophenyl)-4-(dimethyl(phenyl)silyl)-5-
(methoxymethyl)tetrahydrofuran-3-carbaldehyde (10i). Aldehyde
9i (50 mg, 0.271 mmol) was used following the general procedure.
Tetrahydrofuran 10i was obtained as a colorless oil (42 mg, 70%
yield): 1H NMR (CDCl3, 500 MHz) δ 8.65 (d, J = 4.7 Hz, 1H), 7.52−
7.45 (m, 2H), 7.44−7.39 (m, 2H), 7.35 (dd, J = 5.0, 2.1 Hz, 3H),
7.15−7.10 (m, 2H), 5.35 (d, J = 9.0 Hz, 1H), 4.66 (ddd, J = 8.3, 5.1,
3.4 Hz, 1H), 3.37−3.33 (m, 1H), 3.40 (ddd, J = 10.8, 9.0, 4.7 Hz, 1H),
3.35 (dd, J = 10.2, 3.4 Hz, 1H), 3.24 (dd, J = 10.2, 5.2 Hz, 1H), 3.19
(s, 2H), 2.29 (dd, J = 10.8, 7.9 Hz, 1H), 0.37 (s, 3H), 0.31 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 201.6, 137.3, 136.8, 133.7, 131.6, 129.5,
128.0, 127.9, 121.6, 82.3, 81.0, 74.5, 65.8, 58.7, 57.8, 30.9, 15.2, −2.5,
−3.3; IR (film) νmax 2980, 2831, 1718, 1507, 1395, 1251 cm−1. HRMS
(CI, NH3) m/z [M + Na]+ calcd for C21H25BrNaO3Si 455.0654, found
455.0679.
First-Generation Approach toward the Total Synthesis of
(+)-Isatisine A. (2R,3R,4R,5S)-2-(2-Bromostyryl)-4-(dimethyl-
(phenyl)silyl)-5-(methoxymethyl)tetrahydrofuran-3-carbaldehyde
(6a). Ethoxy allyl silane anti-5 (1.3 g, 4.41 mmol) and aldehyde 9a
(1.86 g, 8.82 mmol) were dissolved with methylene chloride (15 mL)
in a round-bottom flask. The mixture was cooled to 0 °C, and PTSA
monohydrate (0.83 g, 4.41 mmol) was added in one portion. The
solution was allowed to stir for 10 min at 0 °C before addition of satd
NaHCO3 solution (10 mL). The mixture was diluted with methylene
chloride (10 mL), and the resulting layers were separated. The organic
layer was dried over magnesium sulfate, filtered, and concentrated in
vacuo to obtain an oil. Purification over silica gel with hexanes/ethyl
acetate (20/1 to 10/1) provided product tetrahydrofuran 6a as a
( )-(2R,3S,4S,5S)-4-(Dimethyl(phenyl)silyl)-5-(methoxymethyl)-2-
phenyltetrahydrofuran-3-carbaldehyde (10f). Aldehyde 9f (28 μL,
0.271 mmol) was used following the general procedure. Tetrahy-
20
1
colorless oil (1.76 g, 87% yield): [α]D = −3.6 (c 1.5, CHCl3); H
NMR (CDCl3, 500 MHz) δ 9.53 (d, J = 3.5 Hz, 1H), 7.50−7.48 (m,
3H), 7.40−7.35 (m, 4H), 7.29 (dt, J = 7.5, 1.0 Hz, 1H), 7.07 (dt, J =
8.0, 2.0 Hz, 1H), 6.97 (d, J = 16.0 Hz, 1H), 6.09 (dd, J = 16.0, 7.0 Hz,
1H) 4.49 (td, J = 7.5, 1.0 Hz, 1H), 4.07 (ddd, J = 8.5, 6.5, 2.5 Hz, 1H),
3.34 (dd, J = 10.5, 2.5, 1H), 3.299 (s, 3H), 3.297 (dd, J = 11.0, 2.0 Hz,
1H), 3.01 (ddd, J = 10.5, 7.0, 3.5 Hz, 1H), 1.92 (dd, J = 9.5, 7.0 Hz,
1H), 0.38 (s, 3H), 0.36 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 200.7,
136.0, 135.8, 133.7, 132.8, 131.7, 129.7, 129.1, 128.0, 127.8, 127.4,
127.2, 123.6, 81.3, 81.2, 74.6, 59.2, 58.2, 28.0, −3.9, −4.6; IR (film)
νmax 2881, 2729, 1719, 1466, 1428, 1254 cm−1; HRMS (CI, NH3) m/z
[M + Na]+ calcd for C23H27BrNaO3Si 481.0811, found 481.0790.
(2R,3R,4R,5S)-2-((E)-2-Bromostyryl)-4-(dimethyl(phenyl)silyl)-5-
(methoxymethyl)tetrahydrofuran-3-carboxamide (13). The alde-
hyde 6a (586 mg, 2.07 mmol) was dissolved in tert-butyl alcohol (12.8
mL). The mixture was cooled to 0 °C, and 2-methylbutane (6.7 mL,
63.8 mmol) was added quickly into the reaction followed by slow
addition of freshly prepared NaClO2−NaH2PO4−H2O (2g-2g-20 mL)
solution (12.8 mL). The yellow reaction mixture was stirred at rt for 3
h before being concentrated under reduced pressure. The residue was
diluted with ethyl acetate and water (ca. 10.0 mL each). The aqueous
layer was acidified with 1 N HCl until pH = 5.0 and extracted with
diethyl ether (3 × 10.0 mL). The combined organic layers were dried
over anhydrous MgSO4 and concentrated under reduced pressure to
give a crude acid as a colorless oil. The crude acid was used for the
next amidation step without purification: 1H NMR (CDCl3, 500
MHz) δ 7.53−7.43 (m, 3H), 7.43−7.32 (m, 4H), 7.19−7.13 (m, 1H),
7.04 (td, J = 7.7, 1.7 Hz, 1H), 6.89 (d, J = 15.7 Hz, 1H), 6.06 (dd, J =
15.7, 7.4 Hz, 1H), 4.40 (td, J = 7.3, 1.1 Hz, 1H), 4.06 (ddd, J = 9.4, 4.8,
2.2 Hz, 1H), 3.49−3.42 (m, 1H), 3.33 (d, J = 0.7 Hz, 3H), 3.29−3.21
1
drofuran 10f was obtained as a colorless oil (40 mg, 83% yield): H
NMR (CDCl3, 500 MHz) δ 8.65 (d, J = 4.5, 1H), 7.51−7.48 (m, 2H),
7.36−7.33 (m, 3H), 7.30−7.27 (m, 2H), 7.25−7.19 (m, 3H), 5.40 (d, J
= 9.0 Hz, 1H), 4.68 (ddd, J = 8.0, 5.0, 3.5 Hz, 1H), 3.40 (ddd, J = 11.0,
9.0, 4.5 Hz, 1H), 3.35 (dd, J = 10.0, 3.5 Hz, 1H), 3.25 (dd, J = 10.0, 5.0
Hz, 1H), 3.19 (s, 3H), 2.34 (dd, J = 10.5, 8.0 Hz, 1H), 0.37 (s, 3H),
0.31 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 202.0, 138.1, 137.0,
133.7, 133.6, 129.4, 129.0, 128.4, 127.9, 127.8, 127.7, 126.1, 82.2, 81.5,
74.4, 58.6, 57.8, 30.7, −2.4, −3.2; IR (film) νmax 2923, 1719, 1427,
1251, 1111 cm−1; HRMS (CI, NH3) m/z [M + Na]+ calcd for
C21H26NaO3Si 377.1549, found 377.1555.
( )-(2R,3S,4S,5S)-4-(Dimethyl(phenyl)silyl)-5-(methoxymethyl)-2-
(p-tolyl)tetrahydrofuran-3-carbaldehyde (10g). Aldehyde 9g (32 μL,
0.271 mmol) was used following the general procedure. Tetrahy-
1
drofuran 10g was obtained as a colorless oil (42 mg, 84% yield): H
NMR (CDCl3, 500 MHz) δ 8.66 (d, J = 4.6 Hz, 1H), 7.54−7.48 (m,
2H), 7.37−7.32 (m, 3H), 7.13 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 7.7 Hz,
2H), 5.38 (d, J = 9.0 Hz, 1H), 4.68 (ddd, J = 8.1, 5.4, 3.6 Hz, 1H),
3.42−3.33 (m, 2H), 3.25 (dd, J = 10.1, 5.3 Hz, 1H), 3.20 (s, 3H), 2.35
(dd, J = 10.8, 7.9 Hz, 1H), 2.29 (s, 3H), 0.37 (s, 3H), 0.31 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 202.2, 137.4, 137.1, 135.1, 133.7, 129.4,
129.1, 128.0, 126.0, 82.1, 81.5, 74.5, 58.7, 57.8, 30.7, 21.1, −2.4, −3.2;
IR (film) νmax 2980, 2829, 1718, 1427, 1251, 1111 cm−1; HRMS (CI,
NH3) m/z [M + Na]+ calcd for C22H28NaO3Si 391.1705, found
391.1694.
( )-(2R,3S,4S,5S)-4-(Dimethyl(phenyl)silyl)-5-(methoxymethyl)-2-
(2-methoxyphenyl)tetrahydrofuran-3-carbaldehyde (10h). Alde-
hyde 9h (37 mg, 0.271 mmol) was used following the general
procedure. Tetrahydrofuran 10h was obtained as a colorless oil (40
I
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The Journal of Organic Chemistry
Featured Article
(m, 1H), 3.16 (t, J = 7.1 Hz, 1H), 1.97 (dd, J = 9.4, 6.9 Hz, 1H), 0.39
(s, 3H), 0.36 (s, 3H).
an atmosphere of Ar, and In(OTf)3 (0.8 g, 1.58 mmol) was added to
the solution. After 10 min, indole (232 mg, 0396 mmol) was added to
the reaction mixture, which was warmed to rt and stirred for 24 h
before addition of satd NaHCO3 (5 mL). Ethyl acetate (10 mL) was
added, the resulting layers were then separated, and the organic layer
was dried over anhydrous magnesium sulfate. After filtration, the
organic layer was concentrated in vacuo. The resultant residue was
purified over silica gel with hexanes/ethyl acetate (2/1) to give 11 as a
fine yellow solid (167 mg, 70%): [α]D = −23.0 (c 1.0, CHCl3); H
NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 7.68−7.55 (m, 2H), 7.51−
7.42 (m, 2H), 7.41−7.25 (m, 6H), 7.22−7.14 (m, 2H), 7.11 (t, J = 2.4
Hz, 1H), 7.04 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 6.55 (s, 1H), 4.80 (dd, J
= 4.7, 1.6 Hz, 1H), 4.21 (td, J = 6.7, 3.5 Hz, 1H), 3.25 (s, 3H), 3.24−
3.12 (m, 2H), 2.80 (dd, J = 4.9, 2.8 Hz, 1H), 1.88 (dd, J = 7.1, 2.9 Hz,
1H), 0.31 (d, J = 10.8 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 199.8,
177.7, 140.3, 136.9, 135.9, 133.9, 132.9, 131.0, 129.6, 128.6, 128.0,
127.0, 124.7, 123.3, 122.4, 120.7, 120.2, 118.8, 113.6, 111.5, 85.9, 82.3,
75.5, 72.6, 59.0, 49.1, 29.7, −4.3, −4.8; IR (film) νmax 3287, 2925,
1699, 1427, 1251 cm−1; HRMS (CI, NH3) m/z [M + Na]+ calcd for
C31H31BrN2NaO4Si 625.1134, found 625.1124.
(2S,3R,3aR,10aR,10bS)-3-(Dimethyl(phenyl)silyl)-10a-(1H-indol-
3-yl)-2-(methoxymethyl)-3,3a-dihydro-2H-furo[2′,3′:3,4]pyrrolo-
[1,2-a]indole-4,10(10aH,10bH)-dione (15). A solution of 11 (220 mg,
0.364 mmol) in anhydrous toluene (7.0 mL) was added into a sealed
tube under an atmosphere of Ar. CuI (35 mg, 0.182 mmol), potassium
carbonate (150 mg, 1.09 mmol), and N,N-dimethylenediamine (39 μL,
0.364 mmol) were successively added under Ar atmosphere. Then the
mixture was warmed to 110 °C and stirred for 12 h. The purple
reaction mixture was cooled to rt and filtered through a short pad of
silica gel with ethyl acetate (20 mL). The filtrate was concentrated
under reduced pressure to give a yellowish solid. Purification over silica
gel with hexanes/ethyl acetate (2/1) afforded 15 as a light yellow solid
(150 mg, 80%): mp 232−234 °C; [α]D20 = +174.2 (c 1.0, CHCl3); 1H
NMR (CDCl3, 500 MHz): δ 8.15 (s, 1H), 8.00 (ddt, J = 17.8, 8.1, 0.7
Hz, 2H), 7.68−7.58 (m, 2H), 7.45 (dd, J = 7.9, 1.5 Hz, 2H), 7.35−
7.25 (m, 4H), 7.22−7.13 (m, 4H), 4.76 (dd, J = 4.0, 0.4 Hz, 1H),
4.17−4.09 (m, 1H), 3.25 (dd, J = 4.0, 2.3 Hz, 1H), 3.05 (dd, J = 10.8,
3.3 Hz, 1H), 2.96 (dd, J = 10.9, 5.1 Hz, 1H), 2.85 (s, 3H), 2.06−2.01
(m, 1H), 0.28 (d, J = 12.6 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ
195.6, 176.1, 151.0, 137.0, 136.4, 135.8, 133.8, 129.7, 128.0, 125.4,
125.3, 125.0, 124.5, 122.8, 122.2, 120.9, 120.5, 116.4, 111.5, 111.3,
83.6, 82.6, 75.6, 74.9, 59.0, 54.3, 30.0, −4.4, −4.7; IR (film) νmax 3352,
2925, 1710, 1601, 1465, 1341, 1250 cm−1; HRMS (CI, NH3) m/z [M
+ H]+ calcd for C31H31N2O4Si 523.2053, found 523.2050.
A mixture of the crude acid and TEA (0.38 mL, 1.92 mmol) in
methylene chloride (60 mL) was treated with ethyl chloroformate
(0.18 mL, 1.92 mmol) at −30 °C. After 30 min, anhydrous NH3 gas
was bubbled through the reaction mixture at the same temperature for
10 min. Then the reaction was warmed to rt, diluted with ethyl acetate
(10.0 mL), and washed with H2O (5.0 mL). The organic layer was
dried over anhydrous magnesium sulfate and concentrated under
reduced pressure to give a yellowish oil. Purification over silica gel with
CH2Cl2/MeOH (50/1) afforded amide 13 as a viscous oil (586 mg,
20
1
20
1
96%): [α]D = +1.3 (c 1.5, CHCl3); H NMR (CDCl3, 500 MHz) δ
7.53−7.49 (m, 2H), 7.48−7.42 (m, 2H), 7.40−7.33 (m, 3H), 7.18 (tt,
J = 7.9, 1.8 Hz, 1H), 7.06−7.01 (m, 1H), 6.90 (dt, J = 16.0, 1.6 Hz,
1H), 6.78 (s, 1H), 6.12 (ddd, J = 15.7, 7.2, 1.9 Hz, 1H), 5.40 (s, 1H),
4.18 (ddt, J = 8.4, 6.6, 1.6 Hz, 1H), 4.12−4.05 (m, 1H), 4.01 (ddd, J =
9.1, 3.4, 2.1 Hz, 1H), 3.59 (dd, J = 10.7, 2.2 Hz, 1H), 3.32 (s, 3H),
3.05 (dd, J = 10.7, 3.1 Hz, 1H), 2.95−2.89 (m, 1H), 2.07−2.00 (m,
1H), 0.41 (s, 3H), 0.38 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
175.7, 136.4, 135.9, 133.9, 132.6, 132.2, 129.7, 129.0, 128.1, 127.8,
127.7, 127.4, 123.5, 81.8, 80.2, 73.1, 59.2, 30.8, 14.5, −4.1, −5.2; IR
(film) νmax 3340, 3188, 2922, 1671, 1467, 1428, 1255 cm−1; HRMS
(CI, NH3) m/z [M + Na]+ calcd for C23H28BrNNaO3Si 496.0920,
found 496.0943.
(2S,3R,3aR,6aS)-6-(2-Bromobenzoyl)-3-(dimethyl(phenyl)silyl)-6-
hydroxy-2-(methoxymethyl)tetrahydro-2H-furo[2,3-c]pyrrol-4(5H)-
one (12). Amide 13 (560 mg, 1.18 mmol) was dissolved in a 9:1
mixture (12 mL) of acetone and H2O at rt. NMO (193 mg, 1.65
mmol) was added to the solution, which was stirred for 5 min at rt.
OsO4 (4 wt % solution in H2O, 0.3 mL, 0.0340 mmol) was then
added, and the reaction mixture was stirred for 14 h at rt. Aqueous satd
Na2S2O3 (12 mL) was added, and the mixture was stirred for
additional 10 min at rt. Ethyl acetate (20 mL) was added, and the
resulting layers were separated. The aqueous layer was extracted with
ethyl acetate (2 × 20 mL). The combined organic layers were dried
over magnesium sulfate, filtered, and concentrated in vacuo to obtain a
brown oil. Purification over silica gel with hexanes/ethyl acetate (1/1)
afforded diol 14 (2:1 mixture of diastereomers) as a viscous oil (440
1
mg, 73%): H NMR (CDCl3, 500 MHz) δ 7.55 (s, 1H) 7.52 (dd, J =
7.9, 1.7 Hz, 1H), 7.50−7.45 (m, 3H), 7.40−7.34 (m, 3H), 7.30- 7.25
(m, 1H), 7.11−7.06 (m, 1H), 5.40 (s, 1H), 5.22 (s, 1H), 3.97 (dt, J =
8.3, 2.1 Hz, 1H), 3.86 (dd, J = 9.3, 5.7 Hz, 1H), 3.80 (dd, J = 9.2, 1.9
Hz, 1H), 3.53 (dd, J = 10.9, 1.8 Hz, 1H), 3.29 (s, 3H), 3.01 (dd, J =
5.7, 3.0 Hz, 1H), 2.96 (dd, J = 11.0, 2.4 Hz, 1H), 1.94 (dd, J = 8.3, 3.1
Hz, 1H), 0.37 (d, J = 5.9 Hz, 6H).
Second-Generation Approach toward the Total Synthesis of
(+)-Iatisine A. (2R, 5R)-Methyl 2-(2-bromostyryl)-5-(methoxymeth-
yl)-2,5-dihydrofuran-3-carboxylate (18). To a solution of tetrahy-
drofuran 6a (0.86 g, 1.87 mmol) in THF (18 mL) was added
phenyltrimethyl tribromide (1.0 g, 2.8 mmol) at rt. The solution was
allowed to stir for 12 h at rt before being cooled to 0 °C. TBAF (1 M
in THF, 1.87 mL, 1.87 mmol) was added dropwise, and the reaction
mixture was stirred for 10 min at 0 °C. Ethyl acetate (50 mL) and
water (10 mL) were added, and the layers were separated. The organic
layer was washed with H2O (3 × 10 mL), dried over magnesium
sulfate, filtered, and concentrated in vacuo (temperature of water bath
must keep below 30 °C) to obtain an unsaturated aldehyde as a
yellowish oil. Since this intermediate aldehyde was unstable under
acidic conditions, it was directly used for the next reaction without
The diol 14 (440 mg, 0.865 mmol) was dissolved in methylene
chloride (8.0 mL), and NaBr (267 mg, 2.60 mmol) and TEMPO (68
mg, 0.433 mmol) were added. A premixed solution of NaOCl (5% in
H2O, 17 mL) and NaHCO3 (272 mg) was added at rt, and the
resulting brown mixture was stirred until it turned light yellow (∼30
min). Methylene chloride (20 mL) and water (5 mL) were added, and
the layers were separated. The organic layer was dried over magnesium
sulfate, filtered, and concentrated in vacuo to obtain a yellowish solid.
Purification over silica gel with hexanes/ethyl acetate (2/1) afforded
hydroxyl lactam 12 as a white solid (260 mg, 64%): [α]D20 = +29.6 (c
1
1.05, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.60−7.54 (m, 2H),
7.52−7.48 (m, 2H), 7.39−7.31 (m, 5H), 7.28 (td, J = 7.8, 1.8 Hz, 1H),
6.52 (s, 1H), 5.62 (s, 1H), 4.71 (d, J = 7.6 Hz, 1H), 4.21 (ddd, J = 8.3,
4.2, 2.7 Hz, 1H), 3.40 (dd, J = 10.5, 2.8 Hz, 1H), 3.22 (s, 3H), 3.10 (t,
J = 7.6 Hz, 1H), 2.90 (dd, J = 10.5, 4.3 Hz, 1H), 1.96 (dd, J = 8.4, 7.6
Hz, 1H), 0.44 (d, J = 4.4 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ
200.0, 175.2, 138.2, 135.7, 133.9, 133.3, 131.6, 129.8, 128.9, 128.1,
126.9, 119.5, 88.8, 84.5, 80.5, 73.1, 58.9, 49.4, 30.8, −3.6, −5.5; IR
(film) νmax 3247, 3069, 2923, 1705, 1427, 1281 cm−1; HRMS (CI,
NH3) m/z [M + Na]+ calcd for C23H26BrNNaO5Si 526.0661, found
526.0663.
1
purification: H NMR (CDCl3, 500 MHz) δ 9.82 (s, 1H), 7.60−7.40
(m, 2H), 7.29−7.17 (m, 1H), 7.14−7.02 (m, 2H), 6.89 (td, J = 2.0, 0.8
Hz, 1H), 6.29 (ddd, J = 15.8, 5.7, 0.8 Hz, 1H), 5.65 (dq, J = 3.8, 1.8
Hz, 1H), 5.16 (ddt, J = 3.9, 2.0, 0.9 Hz, 1H), 3.69 (ddd, J = 10.0, 5.1,
0.9 Hz, 1H), 3.59 (ddd, J = 9.9, 5.3, 0.8 Hz, 1H), 3.43 (s, 3H).
To a solution of the unsaturated aldehyde (1.87 mmol, based on
6a) and NaCN (458 mg, 9.35 mmol) in MeOH (37 mL) was added
MnO2 (dried at 150 °C for 12 h, 4 g, 46.7 mmol) in one portion at 0
°C. The reaction mixture was warmed to rt over a period of 1 h and
stirred for an additional 3 h at rt. The mixture was then filtered
through a pad of Celite, and MeOH was removed under reduced
pressure to give a yellow residue. Ethyl acetate (50 mL) and water (10
(2S,3R,3aR,6R,6aS)-6-(2-Bromobenzoyl)-3-(dimethyl(phenyl)-
silyl)-6-(1H-indol-3-yl)-2-(methoxymethyl)tetrahydro-2H-furo[2,3-
c]pyrrol-4(5H)-one (11). A solution of hydroxyl lactam 12 (200 mg,
0.396 mmol) in anhydrous MeCN (4.0 mL) was cooled to 0 °C under
J
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The Journal of Organic Chemistry
Featured Article
mL) were added, and the layers were separated. The organic layer was
washed with H2O (3 × 10 mL), dried over magnesium sulfate, filtered,
and concentrated in vacuo to obtain an oil. Purification over silica gel
with hexanes/ethyl acetate (10/1) afforded unsaturated methyl ester
18 as an colorless oil (376 mg, 57%, two steps): [α]D20 = +700 (c 1.0,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.50 (td, J = 7.0, 1.5 Hz, 2H),
7.24−7.21 (m, 1H), 7.08−7.04 (m, 2H), 6.08 (t, J = 2.0 Hz, 1H), 6.25
(dd, J = 16.0, 6.5 Hz, 1H), 5.60−5.57 (m, 1H), 5.09−5.06 (m, 1H),
3.74 (s, 3H), 3.60 (dd, J = 10.0, 5.5 Hz, 1H), 3.54 (dd, J = 10.0, 4.5
Hz, 1H), 3.40 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 162.5, 138.8,
136.5, 135.4, 132.7, 131.4, 130.1, 128.7, 127.2, 127.1, 123.7, 84.9, 84.9,
74.8, 59.3, 51.7; IR (film) νmax 2882, 1720, 1465, 1436, 1260 cm−1;
HRMS (CI, NH3) m/z [M + Na]+ calcd for C16H17BrNaO4 375.0208,
found 375.0193.
To a solution of a crude diol (135 mg, 0.302 mmol) and 2,2-
dimethoxypropane (0.37 mL, 3.02 mmol) in acetone (3.0 mL) was
added PTSA monohydrate (29 mg, 0.151 mmol). The reaction
mixture was stirred for 1 h under reflux conditions. After the reaction
mixture was cooled to rt, ethyl acetate (10 mL) and H2O (5 mL) were
added and the layers separated. The organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure to obtain an oil. The resultant residue was purified
over silica gel with hexanes/ethyl acetate (5/1) to give dioxolane 22 as
1
a colorless oil (110 mg, 67%, three steps): H NMR (CDCl3, 500
MHz, major isomer): δ 7.63 (dd, J = 8.0, 1.0 Hz, 1H), 7.41−7.35 (m,
2H), 7.29−7.26 (m, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.93 (d, J = 3.0 Hz,
1H), 4.91 (dd, J = 7.5, 5.5 Hz, 1H), 4.30 (d, J = 7.5 Hz, 1H), 4.23 (td,
J = 5.0, 3.5 Hz, 1H), 3.82 (s, 3H), 3.41 (dd, J = 5.0, 2.0 Hz, 2H), 3.14
1
(2S,5R)-Methyl 2-(2-(2-Bromophenyl)-1,2-dihydroxyethyl)-5-(me-
thoxymethyl)-2,5-dihydrofuran-3-carboxylate (20). Methyl ester 18
(300 mg, 0.849 mmol) was dissolved in an 8:1 mixture (8.0 mL) of
acetone and H2O at rt. NMO (100 mg, 0.849 mmol) was added to the
solution, which was stirred for 5 min at rt. OsO4 (4 wt % solution in
H2O, 207 μL, 0.0340 mmol) was then added, and the reaction mixture
was stirred for 10 h at rt. Aqueous satd Na2S2O3 (8.0 mL) was added,
and the mixture was stirred for an additional 10 min at rt. Ethyl acetate
(20 mL) was added, and the resulting layers were separated. The
aqueous layer was extracted with ethyl acetate (2 × 20 mL). The
combined organic layers were dried over magnesium sulfate, filtered,
and concentrated in vacuo to obtain a crude oil. Purification over silica
gel with hexanes/ethyl acetate (1/1) afforded diol 20 as a viscous oil
(s, 3H), 1.61 (s, 3H), 1.37 (s, 3H); H NMR (CDCl3, 500 MHz,
minor isomer): δ 7.62 (dd, J = 8.0, 1.0 Hz, 1H), 7.43−7.38 (m, 2H),
7.30−7.27 (m, 1H), 5.88 (d, J = 4.0 Hz, 1H), 4.96 (d, J = 3.0 Hz, 1H),
(dd, J = 3.5, 1.0 Hz, 1H), 4.52 (d, J = 1.5 Hz, 1H), 4.35 (td, J = 6.5, 3.5
Hz, 1H), 3.83 (s, 3H), 3.65 (dd, J = 6.5, 2.0 Hz, 2H), 3.45 (s, 3H),
1.60 (s, 3H), 1.35 (s. 3H); 13C NMR (CDCl3, 100 MHz) δ 170.1,
169.8, 153.7, 153.4, 135.8, 134.8, 133.8, 133.4, 131.1, 130.8, 129.2,
128.2, 128.1, 126.7, 122.7, 120.6, 116.6, 116.5, 91.1, 89.4, 86.9, 86.8,
85.2, 84.5, 83.3, 79.7, 79.1, 78.9, 78.3, 71.9, 65.8, 60.3, 59.5, 59.0, 53.2,
53.1, 27.5, 27.4, 25.6, 26.5; IR (film) νmax 2934, 1816, 1745, 1440,
1239 cm−1; HRMS (CI, NH3) m/z [M + H]+ calcd for C20H24BrO9
487.0604, found 487.0607.
(3aS,4S,6S,6aS)-4-(2-(2-Bromophenyl)-2-oxoacetyl)-6-(methoxy-
methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-3a-carboxa-
mide (19). To a solution of carbonate 22 (110 mg, 0.226 mmol) in
MeOH (6 mL) was added potassium carbonate (47 mg, 0.339 mmol)
at rt, and the reaction mixture was stirred for 12 h before addition of 1
N HCl (5 mL) and chloroform (20 mL). The layers were separated,
and the aqueous layer was extracted with chloroform (2 × 50 mL).
The combined organic layers were dried over anhydrous magnesium
sulfate, filtered, and stored on a bench as a solution in chloroform for 2
h at rt to induce lactonization (screened by TLC). Then the organic
layer was concentrated under reduced pressure to give crude 24 as a
colorless oil, which was directly used for the next reaction without
purification: 1H NMR (CDCl3, 500 MHz) δ 7.59 (dd, J = 7.8, 1.7 Hz,
1H), 7.53 (dd, J = 8.0, 1.2 Hz, 1H), 7.33−7.38 (m, 1H), 7.21−7.16
(m, 1H), 5.31−5.25 (m, 1H), 4.77 (dd, J = 10.0, 5.5 Hz, 1H), 4.63 (t, J
= 1.7 Hz, 1H), 4.39−4.34 (m, 1H), 3.72 (dd, J = 10.5, 3.0 Hz, 1H),
3.55 (dd, J = 10.0, 2.5 Hz, 1H), 3.46 (dd, J = 3.6, 3.0 Hz, 2H), 3.29 (s,
2H), 1.59 (s, 3H), 1.58 (s, 3H).
A crude lactone 24 was added to a round-bottom flask followed by
anhydrous NH3 solution (7.0 M in MeOH, 2.3 mL) at rt. The reaction
mixture was stirred for 12 h before removing excess NH3 and MeOH
under reduced pressure. Then the resulting crude amide 25 was
redissolved in methylene chloride (2.3 mL), and NaBr (70 mg, 0.678
mmol) and TEMPO (17 mg, 0.113 mmol) were added. A premixed
solution of NaOCl (5% in H2O, 4.5 mL) and NaHCO3 (72 mg) was
added at rt, and the resulting brown mixture was stirred until it turned
light yellow (∼30 min). Methylene chloride (20 mL) and water (5
mL) were added, and the layers were separated. The organic layer was
dried over magnesium sulfate, filtered, and concentrated in vacuo to
obtain a yellowish solid. Purification over silica gel with hexanes/ethyl
acetate (2/1) afforded aminal 19 as a solid (70 mg, 70%, 3 steps)
Alternative Way to Produce Hydroxyl Lactam 19. Methyl
ester 18 (45 mg, 0.127 mmol) was dissolved in a 2:1 mixture (1.3 mL)
of t-BuOH and H2O at rt. NMO (45 mg, 0.382 mmol) was added to
the solution, which was stirred for 5 min at rt. OsO4 (2.5 wt % solution
in H2O, 64 μL, 0.005 mmol) was then added, and the reaction mixture
was stirred for 48 h at rt. Then 1 N NaOH solution was added to the
reaction mixture, which was stirred for an additional 12 h before
acidification with 1 M HCl and quenching with satd Na2S2O3. Ethyl
acetate (10 mL) and H2O (5 mL) were added and the layers
separated. The organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated under reduced pressure to obtain
crude acid 26 as a mixture of diastereomers.
1
(164 mg, 50%): H NMR (CDCl3, 500 MHz, major isomer): δ 7.60
(dd, J = 11.5, 1.5 Hz, 1H), 7.45 (dd, J = 7.5, 1.0 Hz, 1H), 7.31 (td, J =
7.5, 1.5 Hz, 1H), 7.09 (td, J = 8.0, 1.5 Hz, 1H), 6.86 (t, J = 2.0 Hz,
1H), 5.32−5.30 (m, 1H), 5.25 (d, J = 6.0 Hz, 1H), 5.03−5.00 (m,
1H), 4.14 (d, J = 6.0 Hz, 1H), 4.04 (dd, J = 7.5, 3.5 Hz, 1H), 3.91 (d, J
= 7.0 Hz, 1H), 3.76 (s, 3H), 3.06 (dt, J = 10.5, 2.5 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) δ 163.8, 162.5, 141.5, 141.1, 140.3, 139.1, 135.0,
134.5, 132.9, 132.7, 129.6, 129.4, 129.1, 129.1, 127.8, 127.8, 122.9,
121.7, 88.7, 88.0, 85.5, 84.9, 74.4, 73.9, 73.5, 73.2, 73.0, 70.2, 59.8,
59.7, 52.5, 52.3; IR (film) νmax 3420, 2892, 1723, 1649, 1468, 1267
cm−1; HRMS (CI, NH3) m/z [M + Na]+ calc’d for C16H19BrNaO6
409.0263, found 409.0250.
(3aR,4R,6S,6aS)-Methyl 4-(5-(2-Bromophenyl)-2-oxo-1,3-dioxo-
lan-4-yl)-6-(methoxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d]-
[1,3]dioxole-3a-carboxylate (22). Diol 20 (130 mg, 0.336 mmol) and
DMAP (41 mg, 0.336 mmol) were dissolved in anhydrous methylene
chloride (3.4 mL) under an atmosphere of Ar and cooled to 0 °C.
Carbonyldiimidazole (272 mg, 1.68 mmol) was introduced into the
reaction, which was warmed to rt. After 3 h, methylene chloride (10
mL) and water (5 mL) were added, and layers were separated. The
organic layer was dried over magnesium sulfate, filtered, and
concentrated under reduced pressure to obtain crude carbonate 21
(138 mg) as a colorless oil: 1H NMR (CDCl3, 500 MHz) δ 7.55 (dd, J
= 8.0, 1.2 Hz, 1H), 7.37−7.32 (m, 1H), 7.29 (dd, J = 7.8, 1.8 Hz, 1H),
7.22 (ddd, J = 8.0, 7.2, 1.9 Hz, 1H), 7.01 (t, J = 1.6 Hz, 1H), 6.26 (d, J
= 4.2 Hz, 1H), 5.37 (dt, J = 5.2, 2.2 Hz, 1H), 5.12−5.08 (m, 2H), 3.70
(d, J = 3.4 Hz, 3H), 3.60 (s, 3H), 3.38 (s, 3H).
A solution of crude 21 (138 mg, 0.334 mmol) was dissolved in a 8:1
mixture (3.3 mL) of acetone and H2O at rt. NMO (60 mg, 0.501
mmol) was added to the solution, which was stirred for 5 min at rt.
OsO4 (4 wt % solution in H2O, 1.0 mL, 0.167 mmol) was then added,
and the reaction mixture was stirred for 14 h at rt. Aqueous satd
Na2S2O3 (8.0 mL) was added and the mixture was stirred for
additional 10 min at rt. Ethyl acetate (20 mL) was added, and the
resulting layers were separated. The aqueous layer was extracted with
ethyl acetate (2 × 20 mL). The combined organic layers were dried
over magnesium sulfate, filtered, and concentrated in vacuo to obtain a
1
crude diol as a brown oil (135 mg): H NMR (CDCl3, 500 MHz) δ
7.62 (dd, J = 8.0, 1.2 Hz, 1H), 7.40−7.35 (m, 2H), 7.32 (dd, J = 7.8,
1.9 Hz, 1H), 7.28−7.25 (m, 1H), 5.88 (d, J = 4.7 Hz, 1H), 4.75 (dd, J
= 9.1, 4.7 Hz, 1H), 4.37 (d, J = 8.7 Hz, 1H), 4.15 (d, J = 9.1 Hz, 1H),
3.87−3.84 (m, 1H), 3.83 (s, 3H), 3.51 (dd, J = 10.8, 2.6 Hz, 1H), 3.40
(dd, J = 10.8, 4.4 Hz, 1H), 3.08 (s, 3H).
K
DOI: 10.1021/acs.joc.5b00051
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
To a solution of the crude acid 26 and 2,2-dimethoxypropane (16
μL, 0.127 mmol) in methylene chloride (1.3 mL) was added PTSA
monohydrate (2.4 mg, 0.013 mmol). The reaction mixture was stirred
for 3 h under reflux conditions. After the reaction mixture was cooled
to rt, methylene chloride (10 mL) and H2O (5 mL) were added, and
the resulting layers were separated. The organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure to obtain a brownish oil. The crude material was
directly exposed to the previously described ammonolysis and
oxidation conditions to give hydroxyl lactam 19 (12 mg, 20%, four
steps): [α]D20 = +70 (c 0.50, CHCl3); 1H NMR (CDCl3, 500 MHz) δ
7.59 (td, J = 7.5, 1.5 Hz, 2H), 7.33 (td, J = 7.5, 1.0 Hz, 1H), 7.28 (td, J
= 8.0, 2.0 Hz, 1H), 7.01 (s, 1H), 5.77 (s, 1H), 4.81 (d, J = 1.5 Hz, 1H),
4.80 (s, 1H), 3.56 (td, J = 2.5, 2.0 Hz, 1H) 3.76 (dd, J = 10.5, 3.0 Hz,
1H), 3.46 (dd, J = 10.5, 3.0 Hz, 1H), 3.37 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 198.7, 170.3, 137.4, 133.4, 131.8, 129.1, 126.9, 119.8,
116.2, 93.9, 87.2, 87.0, 86.6, 85.9, 72.7, 59.2, 27.0, 26.0; IR (film) νmax
3280, 2936, 1726, 1430, 1233 cm−1; HRMS (CI, NH3) m/z [M +
Na]+ calcd for C18H20BrNNaO7 464.0321, found 464.0325.
(10 mg, 0.0624 mmol) and 15-crown-5 (20 μL, 0.124 mmol) under an
atmosphere of Ar. The mixture was cooled to −30 °C, and a 1.0 M
solution of BBr3 in CH2Cl2 (187 μL, 0.187 mmol) was added in three
portions every 1 h. The reaction mixture was warmed to 0 °C and
stirred for 12 h. Diethyl ether (5 mL) was added to the reaction
mixture and stirred for 10 min at rt. Ethyl acetate (10 mL) and satd
NaHCO3 (5 mL) were added, the resulting layers were then separated,
and the aqueous layer was extracted with ethyl acetate (2 × 10 mL).
The combined organic layers were dried over anhydrous magnesium
sulfate. After filtration, the organic layer was concentrated in vacuo,
and the residue was purified over silica gel with methylene chloride/
MeOH (50/1 to 20/1 gradient elution) to give 1 as a fine yellowish
solid (6.8 mg, 80%): mp 120−123 °C; [α]D20 = +190 (c 0.40, CHCl3)
1
14
25
[lit. [α]D = −283.15 (c 0.46, MeOH) for (−)-isatisine A; [α]D
=
+274 (c 1.1, MeOH)2a,b for (+)-isatisine A22]: 1H NMR (CD3OD, 500
MHz) δ 7.98 (dd, J = 7.5, 1.0 Hz, 1H), 7.93 (dt, J = 8.0, 1.0 Hz, 1H),
7.76 (td, J = 7.5, 1.0 Hz, 1H), 7.63 (dt, J = 8.0, 1.0 Hz, 1H), 7.35−7.31
(m, 2H), 7.29 (s, 1H), 7.12 (td, J = 7.0, 1.0 Hz, 1H), 7.05 (td, J = 7.0,
1.5 Hz, 1H), 4.89 (s, 1H), 4.06 (d, J = 4.0 Hz, 1H), 3.85 (qd, J = 4.5,
1.5 Hz, 1H), 3.39 (dd, J = 11.5, 5.0 Hz, 1H), 3.32 (dd, J = 12.0, 6.0 Hz,
1H); 13C NMR (CD3OD, 100 MHz) δ 196.8, 174.6, 151.9, 139.1,
137.9, 127.4, 126.9, 126.2, 126.1, 124.6, 123.1, 121.1, 120.6, 117.8,
112.9, 110.6, 89.9, 89.0, 84.7, 76.8, 74.3, 63.2; IR (film) νmax 3389,
2923, 1708, 1610, 1468, 1220 cm−1; HRMS (CI, NH3) m/z [M +
Na]+ calcd for C22H18N2NaO6 429.1063, found 429.1082.
(3aR,4R,6S,6aS)-4-((S)-2-(2-Bromophenyl)-1-(1H-indol-3-yl)-2-ox-
oethyl)-6-(methoxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]-
dioxole-3a-carboxamide (28). A solution of aminal 19 (68 mg, 0.153
mmol) in anhydrous methylene chloride (1.5 mL) was cooled to 0 °C
under an atmosphere of Ar. DMAP (1.9 mg, 0.0153 mmol) and
pyridine (15 μL, 0.184 mmol) were successively added, which was
followed by trifluoroacetic anhydride (26 μL, 0.184 mmol), and the
formation of trifluoroacetic ester was monitored by TLC (approx-
imately 30 min). A solution of indole (90 mg, 0.765 mmol) in
methylene chloride (0.5 mL) was added to the reaction mixture, which
was warmed to rt and stirred for 10 h before addition of satd NaHCO3
(5 mL). Methylene chloride (10 mL) was introduced, and the
resulting layers were then separated and the organic layer was dried
over anhydrous magnesium sulfate. After filtration, the organic layer
was concentrated in vacuo, and the residue was purified over silica gel
with hexanes/ethyl acetate (2/1) to give 28 as a fine yellow solid (68
ASSOCIATED CONTENT
* Supporting Information
■
S
Selected spectral data for all new compounds and X-ray
crystallographic analysis of compound 28. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: panek@bu.edu.
■
20
1
mg, 82%): [α]D = +52 (c 0.50, CHCl3); H NMR (CD3CN, 500
MHz) δ; 9.51 (s, 1H), 7.67−7.65(m, 3H), 7.50 (dd, J = 8.0, 1.0 Hz,
1H), 7.41 (d, J = 8.5 Hz, 1H), 7.34 (td, J = 7.5, 1.0 Hz, 1H), 7.28−7.25
(m, 2H), 7.15 (t, J = 8.0 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 5.18 (d, J =
1.5 Hz, 1H), 4.70 (d, J = 4.0 Hz, 1H), 4.26 (q, J = 5.0 Hz, 1H), 3.54
(qd, J = 11.0, 5.0 Hz, 2H), 3.35 (s, 3H), 1.44 (s, 3H), 1.42 (s, 3H); 13C
NMR (CD3CN, 125 MHz) δ 198.7, 172.7, 140.2, 138.5, 135.0, 133.0,
130.3, 128.3, 125.8, 125.7, 123.6, 121.6, 121.1, 119.1, 114.4, 113.2,
94.5, 86.9, 86.3, 85.9, 73.1, 59.9, 27.7, 26.9; IR (film) νmax 3246, 2931,
1713, 1459, 1246 cm−1; HRMS (CI, NH3) m/z [M + H]+ calcd for
C26H26BrN2O6 541.0974, found 541.0961.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Dr. Paul Ralifo, Dr. Norman Lee, and Dr.
Jeffrey Bacon (Chemical Instrumentation Center at Boston
University) for helpful discussions and assistance with NMR,
HRMS, and X-ray crystallographic analysis experiments.
(3aR,4R,6S,6aS)-4-((S)-1-(1H-Indol-3-yl)-2-oxo-2-phenylethyl)-6-
(methoxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-
3a-carboxamide (29). A solution of 28 (54 mg, 0.10 mmol) in
anhydrous toluene (5 mL) was added into a sealed tube under Ar
atmosphere. CuI (10 mg, 0.05 mmol), potassium carbonate (41 mg,
0.30 mmol), and N,N-dimethylenediamine (11 μL, 0.10 mmol) were
successively added under an atmosphere of Ar. Then the mixture was
warmed to 110 °C and stirred for 12 h. The purple reaction mixture
was cooled to rt and filtered through a short pad of silica gel with ethyl
acetate. The filtrate was concentrated under reduced pressure to give a
yellowish solid. Purification over silica gel with hexanes/ethyl acetate
(2/1) afforded 29 as a light yellow solid (41 mg, 90%): mp 160−163
°C; [α]D = +70.0 (c 0.60, CHCl3); H NMR (CDCl3, 500 MHz) δ
8.15−8.13 (m, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.66−7.62 (m, 2H),
7.33−7.31 (m, 1H), 7.24−7.18 (m, 4H), 4.90 (s, 1H), 4.82 (d, J = 2.0
Hz, 1H), 4.35 (q, J = 2.5 Hz, 1H), 3.34 (dd, J = 10.0, 2.5 Hz, 1H), 3.26
(dd, J = 10.0, 2.5 Hz, 1H), 2.61 (s, 3H), 1.51 (s, 3H), 1.38 (s, 3H); 13C
NMR (CD3OD, 100 MHz) δ 195.8, 171.4, 151.5, 139.2, 137.7, 127.5,
127.0, 126.2, 125.7, 124.2, 123.4, 121.3, 120.8, 118.4, 117.6, 113.0,
111.8, 99.7, 88.6, 87.4, 86.0, 76.7, 73.6, 59.2, 27.4, 26.1; IR (film) νmax
3384, 2933, 1719, 1602, 1468, 1217 cm−1; HRMS (CI, NH3) m/z [M
+ H]+ calcd for C26H25N2O6 461.1713, found 461.1728.
REFERENCES
■
(1) Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Zheng, Y.-T.; Chen, J.-J.;
Zhang, X.-M.; Ma, Y.-B. Org. Lett. 2007, 9, 4127−4129.
(2) (a) Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2010, 75, 6830−
6841. (b) Karadeolian, A.; Kerr, M. A. Angew. Chem., Int. Ed. 2010, 49,
1133−1135. (c) Lee, J.; Panek, J. S. Org. Lett. 2011, 13, 502−505.
(d) Zhang, X.; Mu, T.; Zhan, F.; Ma, L.; Liang, G. Angew. Chem., Int.
Ed. 2011, 50, 6164−6166. (e) Wu, W.; Xiao, M.; Wang, J.; Li, Yi.; Xie,
Z. Org. Lett. 2012, 14, 1624−1627. (f) Kumar, C. V. S.; Puranik, V. G.;
Ramana, C. V. Chem.Eur. J. 2012, 18, 9601−9611. (g) Patel, P.;
Ramana, C. V. J. Org. Chem. 2012, 77, 10509−10515.
20
1
(3) (a) For isolation of goinolactone F, see: Wang, S.; Zhang, Y.-J.;
Chen, R.-Y.; Yu, D.-Q. J. Nat. Prod. 2002, 65, 835−841. (b) For
isolation of harringtonolide, see: Buta, J. G.; Flippen, J. L.; Lusby, W.
R. J. Org. Chem. 1978, 49, 1002−1003.
(4) For the haloetherifications, see: (a) Kang, S. H.; Lee, S. B.; Park,
C. M. J. Am. Chem. Soc. 2003, 125, 15748−15749. For the Pd-
mediated etherifications, see: (b) McDonald, R. I.; Liu, G.; Stahl, S. S.
Chem. Rev. 2011, 111, 2981−3019. (c) Nakhla, J. S.; Kampf, J. W.;
Wolfe, J. P. J. Am. Chem. Soc. 2006, 128, 2893−2901. (d) Wolfe, J. P.;
Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620−1621. For the
conjugate addition, see: (e) Asano, K.; Matsubara, S. J. Am. Chem. Soc.
2011, 133, 16711−16713. For the Prins-type cyclizations, see:
(+)-Isatisine A (1). To a solution of methyl ether 29 (9.6 mg, 0.0208
mmol) in anhydrous methylene chloride (1.0 mL) were added NaI
L
DOI: 10.1021/acs.joc.5b00051
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(f) Chavre, S. N.; Choo, H.; Lee, J. K.; Pae, A. N.; Kim, Y.; Cho, Y. S. J.
Org. Chem. 2008, 73, 7467−7471. (g) Overman, L. E.; Pennington, L.
D. J. Org. Chem. 2003, 68, 7143−7157. (h) Loh, T.-P.; Hu, Q.-Y.; Tan,
K.-T.; Cheng, H.-S. Org. Lett. 2001, 3, 2669−2672. (i) Hanaki, N.;
Link, J. T.; MacMillan, D. W.; Overman, L. E.; Trankle, W. G.;
Wurster, J. A. Org. Lett. 2000, 2, 223−226. For the Mukaiyama-type
annulations, see: (j) Kollmann, S.; Frohlich, R.; Hoppe, D. Synthesis
1991, 113, 7980−7984. (d) Fouque, E.; Rousseau, G.; Seyden-Penne,
J. J. Org. Chem. 1990, 55, 4807−4817.
(18) Ager, D. J.; Fleming, I.; Patel, S. K. J. Chem. Soc., Perkin Trans. 1
1981, 2520−2526.
(19) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc.
1968, 90, 5616−5617.
(20) The low yield in this cascade-like process was mainly attributed
to the low efficiency in the dihydroxylation of the styrene-like olefin of
18. In the stepwise dihydroxylation−protection sequence (Schemes 7
and 8), aminal 19 was prepared through seven steps in 23.8% yield.
(21) Niwa, H.; Hida, T.; Yamada, K. Tetrahedron Lett. 1981, 22,
4239−4240.
2007, 883−892. (k) Bruns, A.; Wibbeling, B.; Frohlich, R.; Hoppe, D.
̈
̈
Synthesis 2006, 3111−3121. (l) Paulsen, H.; Graeve, C.; Hoppe, D.
Synthesis 1996, 145−148. (m) Hoppe, D.; Kramer, T.; Erdbrugger, C.
̈
F.; Egert, E. Tetrahedron Lett. 1989, 30, 1233−1236. For the silyl-
directed [3 + 2]-annulations, see: (n) Mertz, E.; Tinsley, J. M.; Roush,
W. R. J. Org. Chem. 2005, 70, 8035−8046. (o) Tinsley, J. M.; Roush,
W. R. J. Am. Chem. Soc. 2005, 127, 10818−10819. (p) Peng, Z. H.;
Woerpel, K. A. Org. Lett. 2002, 4, 2945−2948. (q) Angle, S. R.; El-
Said, N. A. J. Am. Chem. Soc. 2002, 124, 3608−3613. (r) Micalizio, G.
C.; Roush, W. R. Org. Lett. 2001, 3, 1949−1952. (s) Micalizio, G. C.;
Roush, W. R. Org. Lett. 2000, 2, 461−464. (t) Panek, J. S.; Yang, M. J.
Am. Chem. Soc. 1991, 113, 9868−9870. For the cycloadditions of
donor−acceptor cyclopropanes, see: (u) Smith, A. G.; Slade, M. C.;
Johnson, J. S. Org. Lett. 2011, 13, 1996−1999. (v) Pohlhaus, P. D.;
Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson, J. S. J. Am. Chem. Soc.
2008, 130, 8642−8650.
(22) The discrepancy between the experimental optical rotation and
the literature value is attributed to the moderate level of enantiomeric
purity of epoxide cis-7 (up to 92% ee).
(5) (a) Lowe, J. T.; Panek, J. S. Org. Lett. 2005, 7, 3231−3234.
(b) Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836−9837.
(6) (a) Lowe, J. T.; Youngsaye, W.; Panek, J. S. J. Org. Chem. 2006,
71, 3639−3642. (b) Su, Q.; Panek, J. S. J. Am, Chem. Soc. 2004, 126,
2425−2430.
(7) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391−394.
(8) Zhao, H.; Pagenkopf, B. L. Chem. Commun. 2003, 2592−2593.
(9) Kim, J. H.; Lee, S.; Kwon, M.-G.; Park, Y. S.; Choi, S.-K.; Kwon,
B.-M. Synth. Commun. 2004, 34, 1223−1228.
(10) (a) Smith, M. B.; March, J. March’s Advanced Organic Chemistry
Reactions, Mechanisms, and Structure, 6th ed.; Wiley-Interscience: New
York, 2007; pp 218−219. (b) de Meijere, A. Angew. Chem., Int. Ed.
1979, 18, 809−826.
(11) (a) Qin, H.-L.; Panek, J. S. Org. Lett. 2008, 10, 2477−2479.
(b) Wrona, I. E.; Gabarda, A. E.; Evano, G.; Panek, J. S. J. Am. Chem.
Soc. 2005, 127, 15026−15027.
(12) (a) Tron, G. C.; Pagliai, F.; Grosso, E. D.; Genazzani, A. A.;
Sorba, G. J. Med. Chem. 2005, 48, 3260−3268. (b) Slee, D. H.;
Romano, S. J.; Yu, J.; Nguyen, T. N.; John, J. K.; Raheja, N. K.; Axe, F.
U.; Jones, T. K.; Ripka, W. C. J. Med. Chem. 2001, 44, 2094−2107.
(13) (a) Higuchi, K.; Sato, Y.; Tsuchimochi, M.; Sugiura, K.; Hatori,
M.; Kawasaki, T. Org. Lett. 2009, 11, 197−199. (b) Abid, M.; Teixeira,
L.; Torok, B. Org. Lett. 2008, 10, 933−935. (c) Skarpos, H.; Vorob’eva,
̈
̈
D. V.; Osipov, S. N.; Odinets, I. L.; Breuer, E.; Roschenthaler, G.-V.
̈
Org. Biomol. Chem. 2006, 4, 3669−3674.
(14) (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421−7428. (b) Klapars, A.; Antilla, J. C.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727−7729.
(15) (a) Denmark, S. E.; Hurd, A. R. J. Org. Chem. 2000, 65, 2875−
2886. (b) Comins, D.; Libby, A. H.; Al-awar, R. S.; Foti, C. J. J. Org.
Chem. 1999, 64, 2184−2185. (c) Roberson, C. W.; Woerpel, K. A. J.
Org. Chem. 1999, 64, 1434−1435. (d) Fleming, I.; Henning, R.;
Parker, D. C.; Plaut, H. E.; Sanderson, P. E. J. J. Chem. Soc., Perkin
Trans. 1 1995, 317−337. (e) Murakami, M.; Suginome, M.; Fujimoto,
K.; Nakamura, H.; Andersson, P. G.; Ito, Y. J. Am. Chem. Soc. 1993,
115, 6487−6498.
(16) (a) Adams, D. J.; Blake, A. J.; Cooke, P. A.; Gill, C. D.;
Simpkins, N. S. Tetrahedron Lett. 2002, 58, 4603−4615. (b) Marin, J.;
Didierjean, C.; Aubry, A.; Briand, J.-P.; Guichard, G. J. Org. Chem.
2002, 67, 8440−8449. (c) Semple, J. E.; Rydzewski, R. M.; Gardner,
G. J. Org. Chem. 1996, 61, 7967−7972.
(17) (a) Saleur, D.; Bouillon, J.-P.; Portella, C. J. Org. Chem. 2001,
66, 4543−4548. (b) Haley, M. M.; Biggs, B.; Looney, W. A.;
Gilbertson, R. D. Tetrahedron Lett. 1995, 36, 3457−3460. (c) Billups,
W. E.; Lee, G.-A.; Arney, B. E., Jr.; Whitmire, K. H. J. . Am. Chem. Soc.
M
DOI: 10.1021/acs.joc.5b00051
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