Cascade Michael addition/cycloketalization of cyclic 1,3-dicarbonyl compounds: Important role of the tethered alcohol of α,β-unsaturated carbonyl compounds on reaction rate and regioselectivity

Article abstract of DOI:10.1021/jo501604e

Reactions of α,β-unsaturated aldehydes and cyclic 1,3-dicarbonyl compounds proceed primarily by cascade Knoevenagel condensation/six-π-electron electrocyclization (K6EC, formal [3 + 3] cycloaddition), while α,β-unsaturated ketones usually react with cyclic 1,3-dicarbonyl compounds in a 1,4-addition manner. This paper discloses our findings that under acidic conditions, α,β-unsaturated carbonyl compounds (ketones and aldehydes) with a tethered alcohol react with cyclic 1,3-dicarbonyl compounds in a highly regioselective 1,4-addition fashion via in situ generation of a hypothetical α-methylene cyclic oxonium ion as the reactive Michael acceptor. Our studies uncovered the important effect of the tethered alcohol on the reaction rate and/or efficiency and some new mechanistic aspects of the cascade Michael addition/cycloketalization. Finally, the substrate scope was examined, and 43 analogues of penicipyrone and tenuipyrone were prepared in good to excellent yields.

Full text of DOI:10.1021/jo501604e

Article
pubs.acs.org/joc
Cascade Michael Addition/Cycloketalization of Cyclic 1,3-Dicarbonyl
Compounds: Important Role of the Tethered Alcohol of α,β-
Unsaturated Carbonyl Compounds on Reaction Rate and
Regioselectivity
Hongliang Yao, Liyan Song, Yuan Liu, and Rongbiao Tong*
Department of Chemistry, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong, China
*
S Supporting Information
ABSTRACT: Reactions of α,β-unsaturated aldehydes and cyclic 1,3-dicarbonyl compounds proceed primarily by cascade
Knoevenagel condensation/six-π-electron electrocyclization (K6EC, formal [3 + 3] cycloaddition), while α,β-unsaturated
ketones usually react with cyclic 1,3-dicarbonyl compounds in a 1,4-addition manner. This paper discloses our findings that under
acidic conditions, α,β-unsaturated carbonyl compounds (ketones and aldehydes) with a tethered alcohol react with cyclic 1,3-
dicarbonyl compounds in a highly regioselective 1,4-addition fashion via in situ generation of a hypothetical α-methylene cyclic
oxonium ion as the reactive Michael acceptor. Our studies uncovered the important effect of the tethered alcohol on the reaction
rate and/or efficiency and some new mechanistic aspects of the cascade Michael addition/cycloketalization. Finally, the substrate
scope was examined, and 43 analogues of penicipyrone and tenuipyrone were prepared in good to excellent yields.
INTRODUCTION
■
4
-Hydroxy-2-pyrone is an important scaffold that is present in
numerous natural products with structural diversity and potent
1
biological activities. In fact, many 4-hydroxy-2-pyrone
derivatives have been rigorously studied for potential medicinal
applications as antimicrobial/fungal agents, anticancer agents,
acetylcholinesterase (AChE) inhibitors (Alzheimer’s diseases),
2
and HIV protease inhibitors. For example, natural product
3
arisugacins (e.g., arisugacin A) are potent anti-Alzheimer
agents, and the 6-aryl-4-hydroxy-2-pyrone subunit of arisuga-
cins have been found to be necessary for the biological activity
(Figure 1). Therefore, 4-hydroxy-2-pyrone natural products
with novel structural frameworks have attracted much attention
from the synthetic community for their total synthesis and have
served as a platform for the development of new synthetic
Figure 1. Representative examples of natural products containing a 4-
hydroxy-2-pyrone subunit.
4
strategies/methods.
We recently were attracted by two newly isolated natural
smoothly in the presence of Amberlyst 15 (A-15) to give the
corresponding penicipyrone and tenuipyrone through a cascade7
intermolecular Michael addition/cycloketalization (MACK)
5
6
products, penicipyrone and tenuipyrone, whose structures are
characterized by the presence of an unprecedented polycyclic
acetal/ketal. Our previous synthetic work revealed that the
reaction of 4-hydroxy-6-methyl-2-pyrone (also known as
triacetic acid lactone) and α,β-unsaturated ketones proceeds
Received: July 17, 2014
©
XXXX American Chemical Society
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Scheme 1B). This process, however, is mechanistically
Article
(
compounds are generally slow (12 h to 6 days) at ambient
temperature even with activation of the α,β-unsaturated
compounds using primary or secondary amines through
different from numerous examples in the literature in which
8
−11
Scheme 1. Formal [3 + 3] Cycloaddition and Total
Syntheses of Penicipyrone and Tenuipyrone
formation of iminium ions.
However, further studies of
the MACK sequence led us to discover that the tethered
alcohol of α,β-unsaturated carbonyl compounds plays a critical
role in the reactivity and regioselectivity in the reaction with
cyclic 1,3-dicarbonyl compounds. We herein disclose the results
in full detail and the expansion of the substrate scope in the
synthesis of analogues of penicipyrone and tenuipyrone.
RESULTS AND DISCUSSION
■
Synthesis of Alcohol-Tethered α,β-Unsaturated Car-
bonyl Compounds. To examine the role of the tethered
alcohol of α,β-unsaturated carbonyl compounds in the
reactivity and regioselectivity when they react with cyclic 1,3-
dicarbonyl compounds, we prepared a small series of alcohol-
tethered α,β-unsaturated carbonyl compounds as shown in
Scheme 3. A method similar to that used in our previous
Scheme 3. Synthesis of Alcohol-Tethered α,β-Unsaturated
Ketones/Aldehydes
cyclic 1,3-dicarbonyl compounds (including 4-hydroxy-2-
pyrones) tend to undergo Knoevenagel condensation with
α,β-unsaturated aldehydes followed by six-π-electron electro-
cyclization, a well-established cascade process leading to formal
8
[
3 + 3] cycloadducts (Scheme 1A).
In general, the reaction of cyclic 1,3-dicarbonyl compounds
with α,β-unsaturated aldehydes preferably proceeds in a 1,2-
addition fashion (aldol reaction or Knoevenagel condensation;
8
,9
Scheme 1A), while the alternative 1,4-addition (i.e., Michael
addition) is predominant when α,β-unsaturated ketones are
10
employed as the electrophiles (Scheme 2B,C). The only
Scheme 2. Michael Addition of Cyclic 1,3-Dicarbonyl
Compounds to α,β-Unsaturated Ketones/Aldehydes
7
synthesis was first employed to prepare 6a, 6c, and 6e in low
yields (<25%) over three steps (cf. 1 → 2 → 3 → 6a/6c/6e).
Attempts to improve the yields were unsuccessful because the
12
yield of α-methylenation of lactone 1 was only moderate and
the subsequent methyllithium addition to the resulting lactone
produced a considerable amount of tertiary alcohols as side
products. Inspired by the elegant work by Pihko and co-
13
workers on α-methylenation of aldehydes by organocatalysis,
we set out to explore the α-methylenation of lactols 4, which
type of substrate has not been employed in the literature. We
envisioned that the lactols would be in equilibrium with
hydroxy aldehydes and might undergo a similar α-methylena-
tion. To our delight, the organocatalytic α-methylenation of
lactols 4 proceeded efficiently, and the alcohol-tethered α,β-
unsaturated ketones/aldehydes 6a−f could be prepared readily
on a multigram scale in good to excellent yields in two or four
steps using Pihko’s protocol as the key step. Specifically,
lactones 1 as starting materials were reduced by DIBAL-H, and
exception to this general regioselectivity is the diarylprolinol
ether-catalyzed reaction of cyclic 1,3-dicarbonyl compounds
with α,β-unsaturated aldehydes, which occurs via a highly
regioselective and enantioselective 1,4-conjugate addition to
11
afford bicyclic acetals as the major products (Scheme 2A). In
this case, the 1,2-addition pathway is probably suppressed
significantly by the steric interaction of the bulky diarylprolinol
11c
ether with the nucleophile. Nevertheless, the reactions of
cyclic 1,3-dicarbonyl compounds with α,β-unsaturated carbonyl
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the resulting lactols 4 were subjected to the pyrrolidine-
catalyzed α-methylenation to give the desired products 6b, 6d,
and 6f in excellent yields in only two steps. Methyl ketones 6a,
X-ray diffraction analysis (see the Supporting Information).
Apparently, the competing Knoevenagel condensation/six-π-
electron electrocyclization (K6EC), a cascade process initiated
by 1,2-addition, did not occur. When the tethered alcohol of 6b
was replaced with a methyl group such as in compound 8, the
expected K6EC occurred smoothly in the presence of CSA at
room temperature, leading to bicyclic pyrone 12a in 50% yield
(unoptimized). All of these findings clearly suggested that the
tethered alcohol of the α,β-unsaturated carbonyl compounds
can control the regioselectivity (1,4- vs 1,2-addition) and
accelerate the cascade MACK reaction, which might be
attributed to the in situ formation of a cyclic oxonium ion as
the reactive Michael acceptor.
6
c, and 6e could be prepared in high yields by subsequent
methyllithium addition to the corresponding lactols/aldehydes
b, 6d, and 6f followed by MnO oxidation. One of the many
6
2
obvious advantages of this new route is its operational
simplicity on both large and small scales with higher overall
yields compared with the protocol we used previously (dashed
7
arrow, 1 → 2 → 3 → 6b/6d/6f). In addition, α,β-unsaturated
aldehyde 8 and α,β-unsaturated ketone 9 were also prepared
13
from aldehyde 7 using Pihko’s method for control experi-
ments. It is noteworthy that PCC oxidation of lactols 6b, 6d,
and 6f quantitatively provided the corresponding α-methylene
lactones, which constitutes a new approach for the synthesis of
Interestingly, when δ-hydroxy enone 6c or δ-hydroxy enal 6d
was employed (Scheme 5), the MACK reaction of 10a
12
α-methylene lactones.
Critical Role of the Tethered Alcohol of α,β-
Unsaturated Carbonyl Compounds in the Regioselec-
tivity and Reactivity. In the course of examining the substrate
scope of the cascade MACK developed previously in our lab for
Scheme 5. Cascade MACK of ω/δ-Hydroxy Enones/Enals
7
the total syntheses of penicipyrone and tenuipyrone, we were
very delighted to observe that the reaction of γ′-hydroxy-α,β-
unsaturated ketone 6a with 4-hydroxy-6-methyl-2-pyrone
(
10a) proceeded rapidly at room temperature without
additional acid as a promoter to provide tricyclic acetal 11a
in excellent yield within 30 min (Scheme 4). A-15 or
Scheme 4. Preliminary Discovery of the Effect of the
Tethered Alcohol on the Reaction Rate and Regioselectivity
occurred sluggishly. However, the cascade reaction could be
efficiently promoted at room temperature by the addition of a
catalytic amount of CSA (0.1 equiv) to provide the
corresponding tricyclic ketal 11c or acetal 11d, respectively,
in good yield. Notably, no K6EC adduct was isolated from the
reaction mixture. In the case that ω-hydroxy enone 6e or ω-
hydroxy enal 6f was used, the cascade MACK reaction required
both reflux at 40 °C for 12 h and CSA as the promoter, under
which conditions the desired product 11e or 11f, respectively,
was obtained in good yield. These results revealed that the
length of the alcohol tether has an influence on the rate of the
MACK cascade reaction. As observed in Scheme 4, the tethered
alcohol also controlled the regioselectivity (1,4-addition vs 1,2-
addition) for enal substrates (6d and 6f). It is noteworthy that
the tricyclic ketal 11e and acetal 11f were surprisingly trans-
fused, in contrast to the cis-fused ketals 11a−d. The relative
configurations and carbon skeletons of [6/6/5]-11b, [6/6/6]-
7
7
camphorsulfonic acid (CSA) used in our previous protocol
11c, and [6/6/7]-11e were confirmed by X-ray diffraction
was found to be unnecessary for this substrate. In contrast, the
reaction of 10a with enone 9 lacking a tethered alcohol
occurred sluggishly at room temperature even in the presence
of CSA (0.5 equiv) as the promoter. These results suggested
that the tethered alcohol of 6a is involved mechanistically in the
initial step of the cascade reaction, Michael addition of 10a to
enone 6a. Given the fact that cyclic 1,3-dicarbonyl compounds
analysis (see the Supporting Information), which served as the
basis for proposing the relative configuration of other MACK
adducts.
Mechanism of Cascade Michael Addition/Cycloketal-
ization. In light of the new findings from Schemes 4 and 5, we
proposed that the cascade MACK process may begin with the
formation of cyclic oxonium ion 16 as the Michael acceptor (13
→ 16; Scheme 6b), which is mechanistically different from
most conventional activation pathways of Michael acceptors via
are weak acids (pK = 4.0−5.0), we speculated that the in situ
a
formation of a cyclic oxonium ion might be responsible for the
14
reaction rate acceleration. Enal 6b underwent a similar
iminium formation or Lewis /Brønsted acid coordination to
10
“catalyst-free” cascade MACK process with high efficiency to
the carbonyl oxygen (Scheme 6a). In principle, a mild
Brønsted acid would promote the intramolecular cyclization of
the hydroxy-tethered enone or enal 13 to generate hemiacetal
afford tricyclic acetal 11b as the single isolable product. The
molecular structure of 11b was unambiguously substantiated by
C
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Scheme 6. Possible Intramolecular Activation of the Michael
Acceptor
1,3-cyclopentanedione (10d)] were then performed in a
parallel manner for the synthesis of penicipyrone-like
compounds (Table 1). Most of the reactions proceeded
smoothly to provide the desired MACK products (11a−x,
except for 11w) in good to excellent yields. Their relative
stereochemistry was proposed on the basis of X-ray diffraction
analysis of compounds 11b, 11c, 11e, 11h, 11l, and 11p (see
the Supporting Information). In the case of 11w, it remained
unclear that the cascade MACK reaction of 1,3-cyclo-
pentanedione and 6e was unsuccessful. However, no K6EC
adducts could be isolated from the reaction mixture. It is
particularly noteworthy that the alcohol-tethered α,β-unsatu-
rated aldehydes underwent the cascade MACK instead of
K6EC to provide the polycyclic acetals with similar efficiency as
with their counterpart ketones.
Synthesis of Analogues of Tenuipyrone. Next, we
directed our attention to the synthetic application of the
cascade MACK for preparation of the tenuipyrone-like
spiroketals. A small series of alcohol-tethered enones were
prepared readily in two or four steps as shown in Scheme 8. It
should be noted that the butenolides 25a and 25b could not be
synthesized efficiently from the corresponding commercially
available 2(5H)-furanones through Morita−Baylis−Hillman
and Dess−Martin periodinane (DMP) oxidation, which is a
two-step sequence that could be employed for the syntheses of
23a and 23b from cyclopentenone (22) in high yields.
Therefore, γ-lactones 24a and 24b were used as starting
materials to prepare butenolides 25a and 25b through a four-
step sequence: α-phenylselenation, aldol reaction, selenoxide
elimination, and DMP oxidation. Compounds 23a, 23b, 25a,
and 25b prepared by DMP oxidation of the corresponding
alcohols were unstable in the course of purification by column
chromatography on silica gel and decomposed completely
overnight even when stored in the refrigerator. The instability
of these compounds prevented their purification, exact yield
calculation, and characterization. Therefore, the crude products
with triethylsilyl ether from DMP oxidation (presumably 100%
yield for this step) were freshly prepared and used directly for
the subsequent cascade MACK reaction.
1
5, which would be in equilibrium with cyclic oxonium ion 16
as a highly reactive Michael acceptor. It is noted that a similar
oxonium ion as the Michael acceptor generated in situ from
treatment of 3-(hydroxymethyl)dihydrofuran with BF -Et O,
was proposed in the literature. The rate of formation of cyclic
oxonium ion 16 is primarily governed by the length of the
alcohol tether (five-membered to seven-membered rings),
consistent with our experimental results in Schemes 4 and 5
3
2
15
16
and the well-established ring-closure kinetics.
On the basis of this hypothetical intramolecular activation of
the Michael acceptor, a full mechanistic picture of the cascade
MACK can be proposed, as depicted as Scheme 7. Cyclic
18
Scheme 7. Proposed Mechanism for the Cascade Michael
Addition/Cycloketalization
Gratifyingly, the cascade MACK reactions of the crude
enones 21, 23a, 23b, 25a, and 25b with cyclic 1,3-dicarbonyl
compounds proceeded efficiently with simultaneous desilyla-
tion to provide the polycyclic ketals 26a−t in 60−90% yield, as
shown in Table 2. The relative stereochemistry of the polycyclic
spiroketals was proposed on the basis of X-ray diffraction
analysis of 26b-1, 26d, and 26t (see the Supporting
Information). To our surprise, 25a and 25b (γ-lactones) gave
the corresponding MACK products 26d, 26e, 26i, 26j, 26n,
26o, 26s, and 26t with high diastereoselectivity (dr >15:1),
while the similar MACK reaction of 23a and 23b (cyclo-
pentanones) produced a 5:1 to 1:1 mixture of spiroketals under
identical conditions. It was intriguing that the subtle structural
difference would lead to contrasting outcomes of diastereose-
lectivity (cf. 26b vs 26d). We suspected that different
intermediates such as 27 and 28 might be responsible for the
diastereoselectivity in the course of intramolecular oxa-Michael
cyclization (i.e., spiroketalization). The hypothetical intermedi-
ate 27 could be produced from intermolecular Michael addition
of 10a to 23a followed by dehydrative enol formation, while 28
might be generated from 10a and 25a via formation of an α-
exo-methylene cyclic oxonium ion (similar to 16) followed by
intermolecular Michael addition (similar to the mechanism
proposed in Scheme 7). Intermediate 27 would be
oxonium ion 16 generated in situ in the presence of the
Brønsted acid (note: 10a was the weak acid when CSA was not
employed) would be attacked by 10a (Michael addition) to
produce intermediate enol 17, which would undergo keto/enol
tautomerization followed by protonation to form oxonium ion
1
9. The subsequent intramolecular cycloketalization of 19
17
would proceed in a favorable 6-exo-trig fashion to provide the
tricyclic ketal (or acetal) product. The cis-fused kinetic products
11a−d (6/6/5 and 6/6/6 tricycles) were formed exclusively
under mild acidic conditions, while the seven-membered trans-
fused thermodynamic products 11e and 11f were dominant
under harsher acidic conditions with extended reaction time.
Synthesis of Analogues of Penicipyrone. With a better
understanding of the cascade MACK process, we hoped to
expand the substrate scope and achieve the synthesis of natural
product-like compounds (Table 1). Cascade MACK reactions
of 6a−f and three cyclic 1,3-dicarbonyl compounds [4-
hydroxycoumarin (10b), 1,3-cyclohexanedione (10c), and
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Table 1. Synthesis of Penicipyrone-like Polycyclic Ketals/Acetals via Cascade MACK
Scheme 8. Synthesis of Alcohol-Tethered Enones
(6a and 6b) to four carbons (6e and 6f), which is consistent
with the well-established ring-closure kinetics and supports our
hypothesis that an α-methylene cyclic oxonium ion inter-
mediate is generated in situ as the Michael acceptor. On the
basis of these new findings, a detailed mechanism for the
cascade MACK reaction has been proposed. Finally, 43
analogues of penicipyrone and tenuipyrone were prepared in
good to excellent yields via the cascade MACK process.
Biological studies of these analogues are underway and will be
reported in due course.
EXPERIMENTAL SECTION
■
General Experimental Methods. Reactions were carried out in
oven- or flame-dried glassware under a nitrogen atmosphere, unless
otherwise noted. Tetrahydrofuran (THF) was freshly distilled before
use from sodium using benzophenone as an indicator. Dichloro-
pseudoplanar relative to the incoming oxygen nucleophile,
while the oxygen nucleophile from pyrone of 28 might attack
only one favorable side of the enone because of the presence of
the chiral center. However, further studies on the cascade
MACK reactions are needed to fully elucidate the unusual
diastereoselectivity for different substrates.
methane (CH
hydride (CaH
Cl
) was freshly distilled before use from calcium
2
2
). All of the other anhydrous solvents were dried over 3
2
or 4 Å molecular sieves. Solvents used in workup, extraction, and
column chromatography were used as received from commercial
suppliers without additional purification. H and C NMR spectra
1
13
1
were recorded on a 400 MHz spectrometer (400 MHz for H, 100
MHz for 13C). Chemical shifts are reported in parts per million (ppm)
CONCLUSION
We have studied the cascade Michael addition/cycloketalization
MACK) reaction of cyclic 1,3-dicarbonyl compounds and α,β-
1
■
(
as values relative to the internal chloroform-d (7.26 ppm for H and
13
1
77.16 ppm for C), benzene-d (7.16 ppm for H and 128.06 ppm for
6
1
1
3
3
1
C), or dichloromethane-d
C). Abbreviations for signal coupling are as follows: s, singlet; d,
(5.32 ppm for H and 53.84 ppm for
2
unsaturated carbonyl compounds and found that under acidic
conditions the tethered alcohol of the α,β-unsaturated carbonyl
compounds plays a critical role in the regioselectivity and
reactivity. On the basis of our experimental results, we have
proposed that an α-methylene cyclic oxonium ion might be
generated in situ as the reactive electrophile, which would react
rapidly with cyclic 1,3-dicarbonyl compounds in a highly
regioselective 1,4-addition fashion. In addition, the reaction rate
of the cascade MACK reaction decreased considerably when
the length of the alcohol tether was increased from two carbons
doublet; t, triplet; q, quartet; m, multiplet. Infrared (IR) spectra were
recorded as neat samples (liquid films on KBr plates). HRMS spectra
were recorded with a TOF detector. Melting points (mp) were
recorded on a laboratory melting point apparatus.
Preparation of Compounds 6b, 6d, and 6f. To a solution of
lactone 1 (90 mmol) in hexane/CH Cl (95:5 v/v, 500 mL) at −78
2
2
°
C was added diisobutylaluminum hydride (DIBAL-H) (90 mL, 1.0 M
in hexane, 90 mmol) slowly, and the reaction mixture was stirred at
−78 °C for 1 h. After complete consumption of the starting material as
indicated by TLC, the reaction was quenched by the addition of ethyl
E
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Table 2. Synthesis of Tenuipyrone-like Polycyclic Spiroketals via Cascade MACK
acetate (10 mL) at −78 °C followed by the addition of a saturated
sodium potassium tartrate solution (500 mL). The resulting
suspension was allowed to warm to room temperature with vigorous
stirring for 2 h. The organic layer was collected, and the aqueous layer
was extracted with CH Cl (3 × 300 mL). The combined organic
2H), 2.16−2.13 (m, 2H), 1.42−1.35 (m, 2H), 0.50 (br, 1H, OH). 13C
NMR (100 MHz, CD Cl ) δ: 195.3, 150.2, 135.0, 61.9, 31.4, 24.3.
2
2
+
+
HRMS (TOF, CI ) m/z: calcd for C H O [M + H] 115.0759,
6
11
2
found 115.0764.
Compound 6f. 9.6 g, 84% yield over two steps; colorless oil. IR
2
2
−1
1
fractions were washed with brine, dried over Na SO , and
(neat) cm : 3423, 2941, 2867, 1681, 1442, 1068, 958. H NMR (400
2
4
concentrated under reduced pressure. The resulting crude product
lactol) was used directly for the next step without further purification.
MHz, C D ) δ: 9.24 (s, 1H), 5.69 (s, 1H), 5.36 (s, 1H), 3.45 (t, J = 5.6
6
6
(
Hz, 2H), 2.66 (br, 1H, OH), 2.14−2.11 (m, 2H), 1.40−1.35 (m, 4H).
13
13
Following the similar procedure reported by Pihko, to a solution of
-methylbenzoic acid (1.2 g, 9.0 mmol) in CH Cl (100 mL) were
C NMR (100 MHz, C D ) δ: 194.2, 150.4, 133.4, 62.2, 32.6, 27.8,
6
6
+
+
4
24.4. HRMS (TOF, CI ) m/z: calcd for C H O [M + H] 129.0916,
2
2
7 13 2
added pyrrolidine (1.5 mL, 18 mmol), the crude lactol obtained above,
and aqueous formaldehyde (36.5 wt % in water, 8.0 mL). The mixture
was rapidly heated to 45 °C and stirred for 12 h. After complete
consumption of the starting material as indicated by TLC, the reaction
found 129.0915.
Preparation of Compounds 6a, 6c, and 6e. To a solution of
α,β-unsaturated aldehyde 6b, 6d, or 6f (12 mmol) in diethyl ether
(120 mL) at −78 °C was added MeLi (18.7 mL, 1.6 M in diethyl
ether, 30 mmol) dropwise. The resulting reaction mixture was stirred
at −78 °C for 2 h, and then the reaction was quenched by addition of a
was quenched by addition of a saturated NaHCO solution. The
3
organic layer was collected, and the aqueous layer was extracted with
CH Cl (3 × 40 mL). The combined organic fractions were washed
saturated NH Cl solution (100 mL). The organic layer was collected,
2
2
4
with brine, dried over Na SO , and concentrated under reduced
and the aqueous layer was extracted with diethyl ether (3 × 50 mL).
The combined organic fractions were washed with brine, dried over
Na SO , and concentrated under reduced pressure to afford the crude
2
4
pressure. The resulting residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 1:1) to afford the
desired product.
2
4
diol, which was used directly for oxidation without further purification.
To a solution of the crude diol obtained above in CH Cl (250 mL)
was added activated MnO (21 g) in several portions. After complete
consumption of the starting material as indicated by TLC (about 3 h),
the reaction mixture was filtered through a short pad of Celite, and the
filtrate was concentrated under reduced pressure. The resulting residue
was purified by flash column chromatography on silica gel (hexane/
EtOAc = 1:1) to afford the desired product 6a, 6c, or 6e, respectively.
1
9
1
Compound 6b. 5.7 g, 64% yield over two steps; colorless oil. H
NMR (400 MHz, C D ) δ: 9.14 (s, 1H), 5.66 (d, J = 1.2 Hz, 1H), 5.26
2
2
6
6
2
(
s, 1H), 3.39−3.35 (m, 2H), 2.23−2.20 (m, 2H), 0.76 (br, 1H, OH).
1
3
C NMR (100 MHz, C D ) δ: 194.7, 147.2, 135.8, 60.7, 31.7.
6
6
Compound 6d. 7.4 g, 72% yield over two steps; colorless oil. IR
neat) cm : 3442, 2920, 2851, 1647, 1633, 785. H NMR (400 MHz,
−1
1
(
CDCl ) δ: 9.18 (s, 1H), 5.55 (s, 1H), 5.21 (s, 1H), 3.21 (t, J = 6.4 Hz,
3
F
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7
1
Compound 6a. 1.18 g, 86% yield over two steps; colorless oil. H
NMR (400 MHz, C D ) δ: 5.42 (s, 1H), 5.34 (s, 1H), 3.52 (t, J = 6.4
Compound 23b. 474 mg, 64% overall yield over two steps; yellow
−
1
oil. IR (neat) cm : 2955, 2923, 2875, 2853, 1738, 1704, 1648, 1459,
6
6
1
Hz, 2H), 2.36 (td, J = 6.4, 1.2 Hz, 2H), 1.85 (s, 3H), 1.50 (s, 1H, OH).
1376, 1239, 1099, 973. H NMR (400 MHz, C D ) δ: 7.67 (t, J = 2.8
6 6
1
3
C NMR (100 MHz, C D ) δ: 199.4, 146.6, 126.4, 61.9, 34.8, 25.3.
Hz, 1H), 3.57 (t, J = 6.4 Hz, 2H), 2.97 (t, J = 7.2 Hz, 2H), 1.87−1.79
(m, 4H), 1.63−1.59 (m, 2H), 1.53−1.50 (m, 2H), 1.02 (t, J = 8.0 Hz,
6
6
7
1
Compound 6c. 1.20 g, 79% yield over two steps; colorless oil. H
NMR (400 MHz, C D ) δ: 5.40 (s, 1H), 5.27 (s, 1H), 3.84 (s, 1H,
9
1
(
H), 0.61 (q, J = 8.0 Hz, 6H). 13C NMR (100 MHz, C D ) δ: 203.8,
6 6
6
6
95.9, 170.3, 144.3, 62.8, 41.9, 35.9, 32.7, 26.2, 20.3, 7.1 (3C), 4.9
OH), 3.33 (t, J = 6.4 Hz, 2H), 2.31−2.27 (m, 2H), 1.87 (s, 3H), 1.51−
+
+
.48 (m, 2H). 13C NMR (100 MHz, C D ) δ: 198.9, 149.1, 124.8,
16 29 3
3C). HRMS (TOF, CI ) m/z: calcd for C H O Si [M + H]
1
6
6
6
2
97.1886, found 297.1883.
Preparation of Compounds 25a and 25b. To a solution of γ-
butyrolactone 24a or 24b (0.78 mL, 10 mmol) in THF (10 mL) at
78 °C was added lithium bis(trimethylsilyl)amide (LiHMDS)
solution (11 mL, 1.0 M in THF, 11 mmol) dropwise. After 15 min
of stirring, trimethylsilyl chloride (TMSCl) (1.4 mL, 11 mmol) was
added to the reaction mixture. After the reaction mixture was stirred
for additional 30 min at −78 °C, phenylselenyl chloride (PhSeCl)
98%, 2.2 g, 11 mmol) in 17 mL of THF was added. The reaction
mixture was allowed to warm to room temperature gradually over 2 h,
1.7, 32.3, 27.1, 25.4.
Compound 6e. 1.40 g, 82% yield over two steps; colorless oil. IR
neat) cm : 3421, 2935, 2867, 1670, 1457, 1370, 1259, 1061, 799. H
NMR (400 MHz, CDCl ) δ: 6.00 (s, 1H), 5.77 (s, 1H), 3.62 (t, J = 6.0
Hz, 2H), 2.31 (s, 3H), 2.25 (t, J = 7.2 Hz, 2H), 2.04 (s, 1H, OH),
.58−1.51 (m, 2H), 1.49−1.41 (m, 2H). C NMR (100 MHz,
CDCl ) δ: 200.2, 149.0, 125.4, 62.5, 32.3, 30.2, 26.0, 24.7. HRMS
TOF, CI ) m/z: calcd for C H O [M + H] 143.1072, found
8 15 2
43.1075.
Preparation of Compound 21. To a solution of aldehyde 20
101 mg, 0.50 mmol) in THF (5 mL) at 0 °C was added
vinylmagnesium bromide solution (0.75 mL, 1.0 M in THF, 0.75
mmol) dropwise. After 30 min of stirring, the reaction was quenched
by addition of a saturated NH Cl solution (2 mL). The organic layer
was collected, and the aqueous layer was extracted with diethyl ether
3 × 2 mL). The combined organic fractions were washed with brine,
−1
1
(
−
3
13
1
3
+
+
(
(
1
2
0
and the reaction was quenched by addition of a saturated NH Cl
4
(
solution (20 mL). The organic layer was collected, and the aqueous
layer was extracted with Et O (3 × 20 mL). The combined organic
2
fractions were washed with brine, dried over Na SO , and
2
4
4
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (hexane/EtOAc = 3:1) to
afford the desired product (1.84 g, 76% yield) as an orange oil. To a
solution of the α-phenylselenated lactone (1.2 g, 5.0 mmol) in THF
(
dried over Na SO , and concentrated under reduced pressure to afford
2
4
the crude allylic alcohol, which was used directly for oxidation without
further purification. To a solution of the alcohol obtained above in dry
CH Cl (5 mL) at 0 °C were added NaHCO (168 mg, 2.0 mmol)
and Dess−Martin periodinane (DMP) (424 mg, 1.0 mmol). After
vigorous stirring for 30 min at 0 °C, the reaction mixture was stirred at
room temperature for 30 min until TLC indicated complete
consumption of the starting material. The reaction mixture was
diluted with Et O (3 mL) and poured into a saturated NaHCO3
solution containing excess Na S O . The mixture was stirred until the
solid was completely dissolved. The organic phase was collected;
washed sequentially with a saturated NaHCO solution, water, and
brine; dried over Na SO ; and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel
hexane/EtOAc = 4:1) to afford conjugated ketone 21 (89 mg, 78%
yield over two steps) as a colorless oil. IR (neat) cm : 3095, 2956,
912, 2878, 1702, 1684, 1461, 1412, 1239, 1102, 1012, 744. H NMR
(
17 mL) was added LiHMDS solution (5.5 mL, 1.0 M in THF, 5.5
mmol) dropwise at −78 °C. After the reaction mixture was stirred for
2
2
3
1
2
h, aldehyde 20 (1.3 g, 6.0 mmol) in THF (5 mL) was added. After
0 min of stirring at −78 °C, the reaction was quenched by addition of
a saturated NH Cl solution (15 mL). The aqueous layer was extracted
4
with diethyl ether (3 × 15 mL). The combined organic fractions were
washed with brine, dried over Na SO , and concentrated under
2
4
2
reduced pressure to afford the crude aldol product, which was used
directly for oxidative selenium elimination without further purification.
To a solution of crude aldol product obtained above in THF/EtOAc
2
2
3
3
(
1:1 v/v, 25 mL) were sequentially added NaHCO (4.2 g, 49 mmol)
3
2
4
and hydrogen peroxide (30 wt %, 1.5 mL). After 10 min of stirring at
room temperature, the reaction was quenched by addition of a
(
saturated Na S O solution (25 mL). The organic layer was collected,
−1
2
2
3
and the aqueous layer was extracted with EtOAc (3 × 25 mL). The
combined organic fractions were washed with brine, dried over
Na SO , and concentrated under reduced pressure. The residue was
1
2
(
400 MHz, C D ) δ: 6.09 (dd, J = 17.6, 10.4 Hz, 1H), 5.89 (dd, J =
6
6
2
4
1
2
9
1
7.6, 1.2 Hz, 1H), 5.25 (dd, J = 10.4, 1.2 Hz, 1H), 3.48 (t, J = 6.4 Hz,
H), 2.37 (t, J = 7.2 Hz, 2H), 1.82−1.75 (m, 2H), 0.95 (t, J = 8.0 Hz,
H), 0.54 (q, J = 8.0 Hz, 6H). 13C NMR (100 MHz, C D ) δ: 199.1,
purified by flash column chromatography on silica gel (hexane/EtOAc
3:1) to afford the desired butenolide (precursor for 25a or 25b),
which was subsequently oxidized using DMP to provide the desired
product 25a or 25b, respectively. However, attempts to purify 25a and
25b for spectroscopic characterization were unsuccessful. Therefore,
the crude products 25a and 25b were used directly after DMP
oxidation.
=
6
6
+
36.9, 126.8, 62.0, 35.9, 27.3, 7.1 (3C), 4.8 (3C). HRMS (TOF, CI )
+
m/z: calcd for C H O Si [M + H] 229.1624, found 229.1633.
1
2
25
2
Preparation of Compounds 23a and 23b. To a stirred solution
of 2-cyclopenten-1-one (22) (98%, 213 μL, 2.5 mmol) and aldehyde
0 or its five-carbon homologue (3.0 mmol) in THF (3 mL) was
added (S)-(−)-1,1′-bi-2-naphthol) (BINOL) (98%, 73 mg, 0.25
mmol). The reaction mixture was flushed with nitrogen for 20 min
at room temperature. Tributylphosphine (123 μL, 0.50 mmol) was
added to the reaction mixture. After complete consumption of the
starting material as indicated by TLC (about 12 h), the reaction
mixture was concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (hexane/EtOAc
2
Precursor of 25a. 1.0 g, 71% yield over three steps; colorless oil. IR
−1
(
neat) cm : 3416, 2956, 2914, 2878, 1744, 1648, 1451, 1239, 1065.
1
H NMR (400 MHz, C D ) δ: 6.56−6.54 (m, 1H), 4.48−4.46 (m,
6
6
1
2
=
H), 3.78 (t, J = 2.0 Hz, 2H), 3.63 (br, 1H, OH), 3.47−3.42 (m, 2H),
.10−2.03 (m, 1H), 1.71−1.64 (m, 1H), 1.59−1.55 (m, 2H), 0.97 (t, J
13
8.0 Hz, 9H), 0.56 (q, J = 8.0 Hz, 6H). C NMR (100 MHz, C D )
6
6
δ: 172.8, 144.6, 137.2, 69.6, 67.6, 63.1, 33.5, 29.4, 6.9 (3C), 4.6 (3C).
+
+
HRMS (TOF, CI ) m/z: calcd for C H O Si [M + H] 287.1679,
14
27
4
21
=
2:1) to afford the Morita−Baylis−Hillman adduct, which was
subsequently oxidized using DMP to provide 1,3-diketone 23a or 23b,
respectively, as a yellow oil.
found 287.1672.
Precursor of 25b. 0.97 g, 65% yield over three steps, dr 1:1;
−1
colorless oil. IR (neat) cm : 3426, 3093, 2956, 2914, 2878, 1750,
1
Compound 23a. 458 mg, 65% overall yield over two steps; yellow
1651, 1457, 1415, 1378, 1321, 1239, 1203, 1091, 978, 801, 745. H
−
1
oil. IR (neat) cm : 3062, 2956, 2913, 2877, 1712, 1694, 1603, 1460,
NMR (400 MHz, C D ) δ: 6.65−6.62 (m, 1H), 4.52−4.50 (m, 1H),
6
6
1
1
413, 1240, 1097, 970. H NMR (400 MHz, C D ) δ: 7.68 (t, J = 2.8
4.29−4.23 (m, 1H), 3.68 (br, 1H, OH), 3.48−3.44 (m, 2H), 2.12−
2.06 (m, 1H), 1.74−1.68 (m, 1H), 1.62−1.58 (m, 2H), 0.99−0.95 (m,
6
6
Hz, 1H), 3.62 (t, J = 6.4 Hz, 2H), 3.07 (t, J = 6.4 Hz, 2H), 2.02−1.96
13
(
m, 2H), 1.82−1.79 (m, 2H), 1.56−1.53 (m, 2H), 1.01 (t, J = 8.0 Hz,
9H), 0.79−0.78 (m, 3H), 0.59−0.53 (m, 6H). C NMR (100 MHz,
9
1
H), 0.60 (q, J = 8.0 Hz, 6H). 13C NMR (100 MHz, C D ) δ: 203.7,
C D ) δ: 172.1/172.0, 149.1/149.1, 137.3/137.3, 77.3/77.2, 67.4/67.3,
6 6
6
6
95.8, 170.1, 144.3, 62.2, 38.8, 35.9, 27.0, 26.1, 7.1 (3C), 4.9 (3C).
63.2/63.2, 33.6/33.6, 29.3/29.2, 18.8/18.7, 6.9 (3C)/6.9 (3C), 4.7
+
+
+
HRMS (TOF, CI ) m/z: calcd for C H O Si [M + H] 283.1729,
(3C)/4.7 (3C). HRMS (TOF, CI ) m/z: calcd for C H O Si [M +
H] 301.1835, found 301.1834.
15
27
3
15 29
4
+
found 283.1724.
G
dx.doi.org/10.1021/jo501604e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Cascade Michael Addition/Cycloketalization. General Proce-
dure A. To a solution of α,β-unsaturated carbonyl compound 6a or 6b
Compound 11f. General procedure C; 22 mg, 47% yield; white
−1
solid, mp = 111 °C. IR (neat) cm : 2926, 2859, 1709, 1653, 1585,
1
(
0.2 mmol) in CH Cl2 (2 mL) was added cyclic 1,3-dicarbonyl
1450, 1180, 1104, 992, 913. H NMR (400 MHz, CDCl ) δ: 5.76 (s,
2
3
compound 10a−d (0.3 mmol). After 30 min of stirring, the reaction
1H), 5.02 (d, J = 8.8 Hz, 1H), 3.95−3.84 (m, 2H), 2.63 (dd, J = 16.0,
was quenched by addition of a saturated NaHCO solution (1 mL).
4.8 Hz, 1H), 2.23 (d, J = 16.0 Hz, 1H), 2.17 (s, 3H), 1.93−1.89 (m,
3
13
The organic layer was collected, and the aqueous layer was extracted
with EtOAc (3 × 1 mL). The combined organic fractions were washed
with brine, dried over Na SO , and concentrated under reduced
1H), 1.77−1.67 (m, 3H), 1.58−1.44 (m, 3H). C NMR (100 MHz,
CDCl ) δ: 164.7, 164.6, 160.8, 106.4, 100.1, 98.6, 65.3, 38.0, 30.4, 29.6,
3
+
+
28.4, 27.8, 19.9. HRMS (TOF, CI ) m/z: calcd for C H O [M]
2
4
13 16
4
pressure. The residue was purified by flash column chromatography on
silica gel (hexane/EtOAc = 1:2) to afford the desired product (Table
236.1049, found 236.1055.
Compound 11g. General procedure A; 30 mg, 58% yield; white
−1
1
).
General Procedure B. To a solution of α,β-unsaturated carbonyl
compound 6c, 6d, 21, 23a, 23b, 25a, or 25b (0.2 mmol) in CH Cl (2
solid, mp = 178 °C. IR (neat) cm : 2929, 2853, 1709, 1632, 1171,
1
1003. H NMR (400 MHz, CDCl ) δ: 7.84−7.82 (m, 1H), 7.53−7.49
3
(m, 1H), 7.31−7.24 (m, 2H), 4.14−4.01 (m, 2H), 2.86 (d, J = 18.0
Hz, 1H), 2.74 (dd, J = 18.0, 6.4 Hz, 1H), 2.57−2.51 (m, 1H), 2.18−
2
2
mL) were added cyclic 1,3-dicarbonyl compound 10a−d (0.3 mmol)
and (R)-(−)-10-camphorsulfonic acid (CSA) (0.1−0.5 equiv). After 2
h of stirring, the reaction was quenched by addition of a saturated
13
2.11 (m, 1H), 1.86−1.75 (m, 1H), 1.61 (s, 3H). C NMR (100 MHz,
CDCl
6.8, 67.5, 40.1, 28.3, 22.2, 20.7. HRMS (TOF, CI ) m/z: calcd for
) δ: 163.5, 158.4, 152.8, 131.7, 123.9, 122.9, 116.7, 115.7, 109.4,
3
+
9
NaHCO solution (1 mL). Similar workup as described previously and
3
+
C H O [M] 258.0892, found 258.0898.
purification of the reaction mixture afforded the desired product
15 14
4
22
1
Compound 11h. General procedure A; 33 mg, 68% yield. H
(
Table 1 and Table 2).
NMR (400 MHz, CDCl ) δ: 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.49−7.44
General Procedure C. To a solution of α,β-unsaturated carbonyl
3
(
8
2
(
m, 1H), 7.26−7.20 (m, 2H), 5.67 (d, J = 3.6 Hz, 1H), 4.19 (td, J =
compound 6e or 6f (0.2 mmol) in CH Cl (2 mL) were added the
2
2
.8, 2.8 Hz, 1H), 4.05 (q, J = 8.8 Hz, 1H), 2.80−2.78 (m, 2H), 2.76−
cyclic 1,3-dicarbonyl compound 10a−d (0.3 mmol) and CSA (0.1−0.5
equiv). The reaction mixture was heated to reflux for 12 h (overnight),
and then the reaction was quenched by addition of a saturated
13
.69 (m, 1H), 2.17−2.09 (m, 1H), 1.78−1.67 (m, 1H). C NMR
100 MHz, CDCl ) δ: 163.2, 158.0, 152.6, 131.6, 123.9, 122.7, 116.5,
3
1
1
15.3, 101.7, 97.3, 69.0, 36.6, 27.3, 20.1. The structure of 11h (CCDC
013963) was confirmed by single-crystal X-ray diffraction analysis.
Compound 11i. General procedure B; 39 mg, 72% yield; white
NaHCO solution (1 mL). Similar workup as described previously and
3
purification of the reaction mixture afforded the desired product
(
Table 1).
Compound 11a. General procedure A; 39 mg, 88% yield; colorless
−1
7
solid, mp = 154 °C. IR (neat) cm : 2999, 2940, 2882, 1702, 1631,
1608, 1397, 1111, 992. H NMR (400 MHz, CDCl ) δ: 7.83−7.81 (m,
1
1
3
solid, mp = 98−100 °C. H NMR (400 MHz, CDCl ) δ: 5.71 (s, 1H),
4
Hz, 1H), 2.47−2.40 (m, 1H), 2.17 (s, 3H), 2.11−2.04 (m, 1H), 1.78−
1
1
3
1
3
H), 7.50−7.45 (m, 1H), 7.28−7.22 (m, 2H), 3.94−3.87 (m, 1H),
.82−3.78 (m, 1H), 2.76 (dd, J = 18.0, 6.4 Hz, 1H), 2.45 (dd, J = 18.0,
.07−3.95 (m, 2H), 2.68 (d, J = 17.6 Hz, 1H), 2.58 (dd, J = 18.0, 6.4
.67 (m, 1H), 1.50 (s, 3H). 13C NMR (100 MHz, CDCl ) δ: 165.4,
0.8 Hz, 1H), 2.06−2.01 (m, 1H), 1.79−1.71 (m, 1H), 1.59−1.57 (m,
3
13
2
H), 1.45 (s, 3H), 1.37 (td, J = 12.8, 3.6 Hz, 1H). C NMR (100
63.2, 160.6, 108.8, 100.5, 93.9, 67.4, 40.0, 28.1, 22.1, 19.9, 19.8.
MHz, CDCl ) δ: 163.4, 158.7, 152.8, 131.6, 124.0, 122.6, 116.7, 115.7,
3
Compound 11b. General procedure A; 30 mg, 72% yield; light-
+
−1
103.2, 98.2, 62.7, 34.8, 26.2, 25.1, 25.0, 24.9. HRMS (TOF, CI ) m/z:
yellow solid, mp = 112 °C. IR (neat) cm : 2956, 2903, 2858, 1702,
+
1
calcd for C16
H
17
O
4
[M + H] 273.1127, found 273.1136.
1
1
=
1
(
654, 1588, 1142, 1067, 991. H NMR (400 MHz, C D ) δ: 5.28 (s,
22
6
6
1
Compound 11j. General procedure B; 48 mg, 93% yield. H
H), 4.98 (d, J = 3.6 Hz, 1H), 3.76 (td, J = 8.8, 2.8 Hz, 1H), 3.47 (q, J
8.8 Hz, 1H), 2.49 (d, J = 17.2 Hz, 1H), 2.17 (dd, J = 17.2, 6.4 Hz,
H), 1.78−1.70 (m, 1H), 1.52 (s, 3H), 1.24−1.14 (m, 2H). C NMR
100 MHz, CDCl ) δ: 165.1, 162.9, 160.6, 101.3, 100.2, 94.5, 69.0,
6.6, 27.2, 19.8, 19.3. HRMS (TOF, CI ) m/z: calcd for C H O
M] 208.0736, found 208.0739. The structure of 11b (CCDC
NMR (400 MHz, CDCl ) δ: 7.87−7.85 (m, 1H), 7.54−7.51 (m, 1H),
3
7
3
2
2
1
2
.34−7.27 (m, 2H), 5.55 (d, J = 2.0 Hz, 1H), 4.03−3.97 (m, 1H),
13
.85−3.82 (m, 1H), 2.75 (dd, J = 17.6, 6.0 Hz, 1H), 2.56 (dd, J = 17.2,
3
.8 Hz, 1H), 2.33−2.29 (m, 1H), 1.83−1.77 (m, 1H), 1.73−1.70 (m,
+
3
[
13
11
12
4
H), 1.63−1.60 (m, 1H). C NMR (100 MHz, CDCl ) δ: 163.0,
+
3
58.3, 152.6, 131.6, 123.9, 122.5, 116.6, 115.3, 99.1, 98.3, 62.4, 31.0,
4.5, 23.9, 23.6.
1
013961) was confirmed by single-crystal X-ray diffraction analysis.
7
Compound 11c. General procedure B; 34 mg, 72% yield; colorless
Compound 11k. General procedure C; 29 mg, 50% yield; white
1
solid, mp = 118 °C. H NMR (400 MHz, CDCl ) δ: 5.76 (s, 1H),
−1
3
solid, mp = 142 °C. IR (neat) cm : 2931, 2859, 1708, 1623, 1493,
1
3
.83−3.74 (m, 2H), 2.63 (dd, J = 15.6, 6.4 Hz, 1H), 2.30 (d, J = 15.6
1
452, 1208, 1143, 1060. H NMR (400 MHz, CDCl ) δ: 7.80−7.78
3
Hz, 1H), 2.18 (s, 3H), 1.99−1.93 (m, 1H), 1.76−1.70 (m, 1H), 1.58−
(
3
m, 1H), 7.48−7.44 (m, 1H), 7.26−7.19 (m, 2H), 4.04−3.98 (m, 1H),
13
1
.54 (m, 2H), 1.38 (s, 3H), 1.36−1.29 (m, 1H). C NMR (100 MHz,
.86−3.83 (m, 1H), 2.73 (dd, J = 16.8, 4.8 Hz, 1H), 2.36−2.20 (m,
CDCl ) δ: 165.2, 163.6, 160.5, 102.5, 100.3, 95.4, 62.5, 34.8, 25.4, 25.0,
3
2H), 1.88−1.84 (m, 1H), 1.77−1.63 (m, 3H), 1.54−1.40 (m, 2H),
2
4.9 (2C), 19.8. The structure of 11c (CCDC 929150) was confirmed
13
1
1
2
2
.36 (s, 3H). C NMR (100 MHz, CDCl ) δ: 163.0, 160.6, 152.8,
31.6, 123.8, 122.9, 116.6, 116.0, 109.7, 100.8, 63.8, 39.9, 30.4, 29.1,
8.3, 27.9, 20.0. HRMS (TOF, CI ) m/z: calcd for C H O [M]
3
by single-crystal X-ray diffraction analysis.
Compound 11d. General procedure B; 29 mg, 65% yield; colorless
+
+
1
7
18
4
−1
oil. IR (neat) cm : 2929, 2861, 1708, 1655, 1588, 1449, 1189, 1136,
86.1205, found 286.1214.
Compound 11l. General procedure C; 22 mg, 40% yield; yellow
1
9
1
1
1
1
94. H NMR (400 MHz, CDCl ) δ: 5.80 (s, 1H), 5.35 (d, J = 2.4 Hz,
3
H), 3.89 (td, J = 11.2, 3.2 Hz, 1H), 3.77−3.74 (m, 1H), 2.59 (dd, J =
−1
solid, mp = 126 °C. IR (neat) cm : 2927, 2857, 1711, 1629, 1494,
1
7.2, 6.4 Hz, 1H), 2.39 (dd, J = 17.2, 3.2 Hz, 1H), 2.22−2.18 (m, 4H),
1
392, 1156, 1029. H NMR (400 MHz, CDCl ) δ: 7.79−7.77 (m,
3
13
.74−1.53 (m, 4H). C NMR (100 MHz, CDCl ) δ: 164.9, 163.2,
3
1H), 7.48−7.44 (m, 1H), 7.25−7.20 (m, 2H), 5.16 (d, J = 9.2 Hz,
H), 4.05−4.00 (m, 1H), 3.93−3.90 (m, 1H), 2.76 (dd, J = 16.8, 4.8
Hz, 1H), 2.34 (dd, J = 16.8, 12.8 Hz, 1H), 2.19−2.11 (m, 1H), 1.95−
60.5, 99.9, 97.8, 96.2, 62.3, 31.0, 23.8, 23.6, 23.5, 19.8. HRMS (TOF,
1
+
+
CI ) m/z: calcd for C H O [M + H] 223.0970, found 223.0975.
12
15
4
1
3
Compound 11e. General procedure C; 40 mg, 79% yield; light-
1
.91 (m, 1H), 1.83−1.71 (m, 4H), 1.62−1.51 (m, 1H). C NMR
−1
yellow solid, mp = 133 °C. IR (neat) cm : 2929, 2858, 1708, 1651,
(100 MHz, CDCl ) δ: 162.8, 160.0, 152.7, 131.6, 123.9, 122.8, 116.5,
3
1
1
3
1
1
1
1
2
576, 1205, 1137, 1068. H NMR (400 MHz, CDCl ) δ: 5.71 (s, 1H),
115.5, 106.9, 101.3, 65.3, 38.0, 30.4, 29.6, 29.2, 27.9. HRMS (TOF,
3
+
+
.95−3.88 (m, 1H), 3.78−3.74 (m, 1H), 2.56 (dd, J = 16.0, 4.0 Hz,
CI ) m/z: calcd for C H O [M + H] 273.1127, found 273.1137.
16 17 4
H), 2.20−2.05 (m, 5H), 1.83−1.79 (m, 1H), 1.73−1.56 (m, 3H),
The structure of 11l (CCDC 1013964) was confirmed by single-
crystal X-ray diffraction analysis.
13
.50−1.36 (m, 2H), 1.27 (s, 3H). C NMR (100 MHz, CDCl ) δ:
3
23
65.2, 164.7, 160.6, 109.0, 100.6, 98.0, 63.6, 39.7, 30.3, 29.0, 27.8, 27.5,
Compound 11m. General procedure A; 34 mg, 82% yield; yellow
+
+
1
9.8 (2C). HRMS (TOF, CI ) m/z: calcd for C H O [M]
50.1205, found 250.1206. The structure of 11e (CCDC 1013962)
oil. H NMR (400 MHz, CDCl ) δ: 4.06−4.00 (m, 1H), 3.97−3.91
1
4
18
4
3
(m, 1H), 2.58 (d, J = 16.4 Hz, 1H), 2.38−2.31 (m, 6H), 2.04−1.92
(m, 3H), 1.75−1.64 (m, 1H), 1.46 (s, 3H). C NMR (100 MHz,
13
was confirmed by single-crystal X-ray diffraction analysis.
H
dx.doi.org/10.1021/jo501604e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CDCl ) δ: 198.8, 169.5, 108.3, 106.9, 67.3, 40.0, 36.8, 28.8, 28.2, 22.1,
J = 11.2, 3.2 Hz, 1H), 3.79−3.75 (m, 1H), 2.62−2.57 (m, 2H), 2.46−
3
2
1.1, 18.9.
2.43 (m, 2H), 2.37−2.31 (m, 1H), 2.17−2.09 (m, 2H), 1.79−1.64 (m,
2
4
13
Compound 11n. General procedure A; 34 mg, 88% yield; light-
3H), 1.53−1.46 (m, 1H). C NMR (100 MHz, CDCl ) δ: 203.9,
3
1
yellow oil. H NMR (400 MHz, CDCl ) δ: 5.41 (d, J = 4.0 Hz, 1H),
182.4, 112.9, 100.1, 62.4, 33.4, 30.8, 26.0, 23.9, 23.6, 21.3.
3
4
2
1
1
.14 (td, J = 8.8, 2.4 Hz, 1H), 3.97 (q, J = 8.8 Hz, 1H), 2.57−2.55 (m,
Compound 11x. General procedure C; 9 mg, 20% yield; white
−1
H), 2.40−2.34 (m, 5H), 2.06−2.01 (m, 1H), 2.00−1.91 (m, 2H),
solid, mp = 96 °C. IR (neat) cm : 2927, 2856, 1689, 1627, 1392,
1
3
1
.70−1.60 (m, 1H). C NMR (100 MHz, CDCl ) δ: 198.6, 169.2,
1181, 1155. H NMR (400 MHz, CDCl ) δ: 5.10 (d, J = 8.4 Hz, 1H),
3
3
07.5, 101.1, 68.9, 36.8, 36.7, 28.6, 27.4, 21.0, 18.4.
4.00−3.87 (m, 2H), 2.56−2.54 (m, 2H), 2.46−2.36 (m, 3H), 1.97−
1
3
Compound 11o. General procedure B; 32 mg, 71% yield; yellow
1.91 (m, 3H), 1.81−1.67 (m, 4H), 1.55−1.50 (m, 1H). C NMR
−1
1
oil. IR (neat) cm : 2939, 2864, 1654, 1622, 1393, 1110, 1046, 985. H
NMR (400 MHz, CDCl ) δ: 3.82−3.69 (m, 2H), 2.44−2.28 (m, 5H),
(100 MHz, CDCl ) δ: 203.4, 184.4, 115.9, 108.4, 65.4, 38.0, 34.0, 30.4,
3
+
29.7, 28.0, 26.1, 25.5. HRMS (TOF, CI ) m/z: calcd for C H O [M
+ H] 209.1178, found 209.1183.
Compound 12a. General procedure B; reaction of 8 and 4-
3
12 17
3
+
2
1
1
3
.18 (d, J = 15.6 Hz, 1H), 2.00−1.94 (m, 2H), 1.86−1.83 (m, 1H),
26
.71−1.66 (m, 1H), 1.56−1.47 (m, 2H), 1.32 (s, 3H), 1.29−1.21 (m,
H). 13C NMR (100 MHz, CDCl ) δ: 198.7, 169.6, 108.4, 102.0, 62.4,
hydroxy-6-methyl-2-pyrone (10a) for 2 h afforded 12a in 50% yield
3
+
−1
6.8, 34.8, 28.6, 25.0, 24.9, 24.8, 24.4, 21.1. HRMS (TOF, CI ) m/z:
(20 mg) as an amorphous solid. IR (neat) cm : 2960, 2924, 2873,
+
1
calcd for C H O [M] 222.1256, found 222.1263.
2852, 1641, 1587, 1571, 1465, 1262, 1144, 1007. H NMR (400 MHz,
13
18
3
Compound 11p. General procedure B; 32 mg, 76% yield; colorless
CDCl ) δ: 6.19 (s, 1H), 5.77 (s, 1H), 4.78 (s, 2H), 2.21 (s, 3H), 2.00
3
−1
13
solid, mp = 80 °C. IR (neat) cm : 2938, 2868, 1624, 1388, 1147,
(t, J = 8.0 Hz, 2H), 1.53−1.47 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H).
C
1
1
3
2
2
089, 935. H NMR (400 MHz, CDCl ) δ: 5.24 (d, J = 2.8 Hz, 1H),
NMR (100 MHz, CDCl ) δ: 163.6, 162.7, 161.8, 129.5, 112.3, 99.8,
3
3
+
.92−3.86 (m, 1H), 3.74−3.69 (m, 1H), 2.45−2.41 (m, 2H), 2.38−
99.6, 69.8, 35.1, 20.2, 19.9, 13.9. HRMS (TOF, CI ) m/z: calcd for
C H O [M] 206.0943, found 206.0950.
+
.35 (m, 2H), 2.31−2.22 (m, 2H), 2.12−2.06 (m, 1H), 2.00−1.93 (m,
12
14
3
13
27
H), 1.69−1.65 (m, 3H), 1.55−1.49 (m, 1H). C NMR (100 MHz,
Compound 12b. General procedure B; reaction of 9 and 10a for
CDCl ) δ: 198.3, 169.1, 109.3, 97.6, 62.5, 36.7, 31.0, 28.1, 23.7, 23.6,
48 h afforded 12b in <10% yield (5 mg) as an amorphous solid. IR
3
+
+
−1
2
2
2.4, 20.9. HRMS (TOF, CI ) m/z: calcd for C H O [M]
(neat) cm : 3441, 2958, 2925, 2872, 2853, 1681, 1585, 1451, 1409,
1
2
16
3
1
08.1099, found 208.1104. The structure of 11p (CCDC 1013966)
1381, 1251, 1064, 995, 833. H NMR (400 MHz, CDCl
) δ: 9.22 (s,
3
was confirmed by single-crystal X-ray diffraction analysis.
1H, OH), 5.81 (s, 1H), 2.97−2.92 (m, 1H), 2.58 (dd, J = 14.0, 10.8
Compound 11q. General procedure C; 28 mg, 60% yield; light-
Hz, 1H), 2.46 (dd, J = 14.0, 2.0 Hz, 1H), 2.21−2.17 (m, 6H), 1.80−
−1
13
yellow oil. IR (neat) cm : 2930, 2858, 1650, 1614, 1386, 1137, 1097,
1.74 (m, 2H), 1.44−1.37 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H). C NMR
1
1
(
1
1
056. H NMR (400 MHz, CDCl ) δ: 3.98−3.92 (m, 1H), 3.80−3.75
(100 MHz, CDCl ) δ: 217.9, 166.1, 166.0, 160.7, 101.4, 101.3, 52.2,
3
3
+
m, 1H), 2.50−2.45 (m, 1H), 2.39−2.29 (m, 4H), 2.01−1.88 (m, 4H),
34.8, 28.9, 23.2, 19.9, 19.8, 14.2. HRMS (TOF, CI ) m/z: calcd for
+
.83−1.79 (m, 1H), 1.74−1.71 (m, 1H), 1.65−1.55 (m, 2H), 1.45−
C
13
H
18
O
4
[M] 238.1205, found 238.1204.
.36 (m, 2H), 1.25 (s, 3H). 13C NMR (100 MHz, CDCl ) δ: 198.2,
Compound 26a. General procedure B; 39 mg, 88% yield; colorless
3
−
1
1
71.5, 111.7, 108.6, 63.6, 39.9, 36.7, 30.6, 29.2, 28.8, 27.9, 26.8, 21.1,
oil. IR (neat) cm : 2955, 2912, 2877, 1724, 1586, 1236, 1073, 1004.
+
+
1
19.8. HRMS (TOF, CI ) m/z: calcd for C H O [M] 236.1412,
H NMR (400 MHz, CDCl ) δ: 5.69 (s, 1H), 4.11−4.06 (m, 1H),
3
14
20
3
found 236.1413.
4.04−3.98 (m, 1H), 2.63−2.49 (m, 2H), 2.24−2.17 (m, 5H), 2.06−
13
Compound 11r. General procedure C; 16 mg, 35% yield; white
2.00 (m, 2H), 1.98−1.84 (m, 2H). C NMR (100 MHz, CDCl ) δ:
3
−1
solid, mp = 96 °C. IR (neat) cm : 2928, 2859, 1731, 1650, 1617,
164.8, 163.2, 160.1, 108.8, 100.6, 98.2, 69.0, 36.7, 29.1, 23.7, 19.7, 16.9.
1
+
+
1
388, 1177, 1152, 1086, 935. H NMR (400 MHz, CDCl ) δ: 4.90 (d,
HRMS (TOF, CI ) m/z: calcd for C H O [M + H] 223.0970,
3
12 15 4
J = 8.4 Hz, 1H), 3.97−3.91 (m, 1H), 3.86−3.82 (m, 1H), 2.54−2.51
found 223.0979.
(
m, 1H), 2.41−2.38 (m, 2H), 2.35−2.30 (m, 2H), 1.99−1.83 (m, 6H),
Compound 26b (Separable Diastereomers). General procedure B;
49 mg, 88% yield, dr 1.5:1. Major diastereomer (26b-1): light-yellow
solid, mp = 149 °C. IR (neat) cm : 2960, 2894, 1741, 1707, 1654,
1
3
1
.72−1.64 (m, 2H), 1.48−1.42 (m, 2H). C NMR (100 MHz,
−1
CDCl ) δ: 198.2, 170.8, 112.1, 106.3, 65.2, 38.2, 36.6, 30.6, 29.8, 28.3,
7.9, 27.8, 21.0. HRMS (TOF, CI ) m/z: calcd for C H O [M +
H] 223.1329, found 223.1326.
Compound 11s. General procedure A; 16 mg, 40% yield; white
solid, mp = 116 °C. IR (neat) cm : 2926, 2855, 1678, 1617, 1407,
179, 1101, 1003. H NMR (400 MHz, CDCl ) δ: 4.09 (td, J = 8.8,
3
+
1
2
1590, 1405, 1055. H NMR (400 MHz, C D ) δ: 5.23 (s, 1H), 3.63−
13
19
3
6
6
+
3.58 (m, 1H), 3.47−3.42 (m, 1H), 3.00 (q, J = 9.6 Hz, 1H), 2.79−2.64
(m, 2H), 2.14 (d, J = 9.6 Hz, 1H), 2.06−2.01 (m, 2H), 1.92−1.78 (m,
−1
13
2H), 1.75−1.66 (m, 1H), 1.55 (s, 3H), 1.47−1.43 (m, 1H). C NMR
1
1
2
(
1
1
(100 MHz, C D ) δ: 214.2, 163.2, 160.8, 160.7, 107.2, 101.6, 99.7,
3
6
6
+
.8 Hz, 1H), 4.00 (q, J = 8.8 Hz, 1H), 2.60−2.48 (m, 2H), 2.44−2.41
69.9, 47.4, 37.9, 35.0, 32.3, 27.2, 23.1, 19.3. HRMS (TOF, CI ) m/z:
+
m, 3H), 2.38−2.32 (m, 2H), 2.07−2.00 (m, 1H), 1.74−1.63 (m, 1H),
calcd for C H O [M + H] 277.1076, found 277.1082. The
15
17
5
.52 (s, 3H). 13C NMR (100 MHz, CDCl ) δ: 204.4, 182.6, 111.5,
structure of 26b-1 (major isomer, CCDC 1013972) was confirmed by
single-crystal X-ray diffraction analysis. Minor diastereomer (26b-2):
light-yellow solid, mp = 136 °C. IR (neat) cm : 2956, 2922, 1742,
1706, 1652, 1581, 1073. H NMR (400 MHz, C D ) δ: 5.16 (s, 1H),
3
+
10.2, 67.6, 39.9, 33.4, 28.1, 26.6, 22.2, 17.4. HRMS (TOF, CI ) m/z:
calcd for C H O [M + H] 195.1021, found 195.1028.
+
−1
11
15
3
1
Compound 11t. General procedure A; 24 mg, 67% yield; light-
6
6
−1
yellow solid, mp = 98 °C. IR (neat) cm : 2927, 1679, 1619, 1410,
3.65−3.57 (m, 2H), 3.51−3.45 (m, 1H), 2.82 (dt, J = 12.8, 4.8 Hz,
1H), 2.67 (ddd, J = 14.0, 8.4, 3.2 Hz, 1H), 2.04 (d, J = 7.6 Hz, 1H),
1.94 (dt, J = 14.0, 9.6 Hz, 1H), 1.84−1.74 (m, 3H), 1.65−1.58 (m,
1
1
4
3
117, 1066. H NMR (400 MHz, CDCl ) δ: 5.57 (d, J = 7.2 Hz, 1H),
3
.18 (td, J = 8.4, 1.2 Hz, 1H), 4.01 (q, J = 8.4 Hz, 1H), 2.59−2.51 (m,
13
13
H), 2.42−2.39 (m, 4H), 2.08−2.01 (m, 1H), 1.68−1.57 (m, 1H).
C
1H), 1.44 (s, 3H), 1.36−1.32 (m, 1H). C NMR (100 MHz, C D ) δ:
6
6
NMR (100 MHz, CDCl ) δ: 204.2, 182.3, 110.8, 103.7, 69.1, 36.5,
213.1, 163.9, 162.6, 161.1, 107.7, 100.5, 100.2, 67.6, 54.5, 35.6, 35.3,
3
+
+
3
[
3.3, 27.3, 26.4, 17.1. HRMS (TOF, CI ) m/z: calcd for C H O
M] 180.0786, found 180.0789.
Compound 11u. General procedure B; 37 mg, 90% yield; yellow
32.9, 23.9, 23.8, 19.1. HRMS (TOF, CI ) m/z: calcd for C H O
10
12
3
15 16
5
+
+
[M] 276.0998, found 276.1001.
Compound 26c (Inseparable Diastereomers). General procedure
B; 52 mg, 89% yield, dr 5:1. Major diastereomer: light-yellow solid, mp
= 140−143 °C. IR (neat) cm : 2949, 2881, 1743, 1711, 1654, 1592,
1446, 1405, 1125, 1105, 1071, 1045. H NMR (400 MHz, CDCl ) δ:
−1
1
oil. IR (neat) cm : 2929, 2861, 1629, 1404, 1118, 1076. H NMR
−1
(
2
400 MHz, C D ) δ: 3.68−3.61 (m, 1H), 3.51−3.47 (m, 1H), 2.17−
6
6
1
.01 (m, 4H), 1.98−1.92 (m, 2H), 1.32−1.25 (m, 2H), 1.17 (s, 3H),
3
13
1
.05−1.02 (m, 1H), 0.99−0.97 (m, 2H). C NMR (100 MHz, C D )
5.78 (s, 1H), 3.53−3.46 (m, 2H), 3.08−3.01 (m, 1H), 2.62−2.52 (m,
6
6
δ: 201.8, 181.1, 111.9, 104.9, 62.2, 34.8, 33.7, 26.1, 25.3, 25.0, 24.9,
1H), 2.35−2.21 (m, 2H), 2.17−2.09 (m, 5H), 1.85−1.76 (m, 2H),
+
+
13
2
2
3.2. HRMS (TOF, CI ) m/z: calcd for C H O [M + H]
1.61−1.57 (m, 2H), 1.47−1.42 (m, 2H). C NMR (100 MHz,
1
2
17
3
09.1188, found 209.1178.
CDCl ) δ: 215.9, 164.1, 160.7, 160.4, 101.6, 99.9, 98.7, 62.1, 50.6, 37.9,
3
2
5
1
Compound 11v. General procedure B; 34 mg, 87% yield; yellow
31.4, 30.6, 26.8, 23.9, 19.7, 17.7. Minor diastereomer: H NMR (400
1
oil. H NMR (400 MHz, CDCl ) δ: 5.42 (d, J = 2.4 Hz, 1H), 3.91 (td,
MHz, CDCl ) δ: 5.71 (s, 1H), 3.53−3.46 (m, 2H), 2.62−2.52 (m,
3
3
I
dx.doi.org/10.1021/jo501604e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
+
+
4
1
H), 2.35−2.21 (m, 2H), 2.17−2.09 (m, 3H), 1.85−1.76 (m, 2H),
HRMS (TOF, CI ) m/z: calcd for C H O [M] 326.1154, found
19 18 5
326.1157.
13
.61−1.57 (m, 2H), 1.47−1.42 (m, 2H). C NMR (100 MHz,
CDCl ) δ: 214.1, 163.4, 163.3, 161.2, 100.9, 100.4, 98.4, 62.2, 55.3,
Compound 26i. General procedure B; 53 mg, 84% yield; white
solid, mp = 214 °C. IR (neat) cm : 2958, 2924, 2854, 1775, 1707,
1633, 1395, 1163, 1078, 1035, 1009. H NMR (400 MHz, C
3
+
−1
36.6, 31.8, 31.1, 24.5, 22.8, 19.6, 17.5. HRMS (TOF, CI ) m/z: calcd
+
1
for C H O [M] 290.1154, found 290.1148.
6
D
6
) δ:
16
18
5
Compound 26d. General procedure B; 43 mg, 78% yield; yellow
7.44−7.42 (m, 1H), 6.91−6.83 (m, 2H), 6.76−6.72 (m, 1H), 4.54 (d, J
= 9.2 Hz, 1H), 3.86 (dd, J = 9.6, 5.6 Hz, 1H), 3.48−3.38 (m, 3H), 2.81
(ddd, J = 16.0, 8.0, 3.6 Hz, 1H), 2.19 (d, J = 8.4 Hz, 1H), 1.97 (dt, J =
−1
solid, mp = 164 °C. IR (neat) cm : 2958, 2922, 2855, 1774, 1703,
1
1
5
1
2
1
1
3
2
651, 1588, 1210, 1150, 1021, 993. H NMR (400 MHz, C D ) δ:
6 6
1
3
.04 (s, br, 1H), 4.66 (d, J = 9.6 Hz, 1H), 3.81 (dd, J = 9.6, 4.8 Hz,
H), 3.59−3.53 (m, 1H), 3.46−3.38 (m, 2H), 2.76−2.69 (m, 1H),
.13 (d, J = 8.4 Hz, 1H), 1.93 (dt, J = 14.0, 9.6 Hz, 1H), 1.79−1.72 (m,
13.6, 10.0 Hz, 1H), 1.80−1.73 (m, 1H), 1.51−1.44 (m, 1H). C NMR
(100 MHz, C ) δ: 172.6, 161.1, 159.1, 153.4, 131.9, 123.7, 122.6,
116.8, 115.8, 107.2, 102.0, 70.1, 68.4, 45.9, 35.2, 33.1, 23.7. HRMS
D
6
6
+
+
1
3
(
TOF, CI ) m/z: calcd for C H O [M] 314.0790, found 314.0796.
H), 1.48−1.42 (m, 1H), 1.36 (s, 3H). C NMR (100 MHz, C D ) δ:
17 14 6
6
6
Compound 26j. General procedure B; 56 mg, 85% yield; white
72.7, 163.9, 162.8, 161.8, 106.7, 100.1, 98.4, 69.9, 68.3, 46.1, 35.3,
2.6, 23.8, 19.2. HRMS (TOF, CI ) m/z: calcd for C H O [M]
−1
+
+
solid, mp = 181 °C. IR (neat) cm : 2964, 2933, 2901, 1777, 1708,
14
14
6
1
1
7
632, 1397, 1166, 1056, 1029. H NMR (400 MHz, C D ) δ: 7.46−
78.0790, found 278.0787. The structure of 26d (CCDC 1013967)
was confirmed by single-crystal X-ray diffraction analysis.
6
6
.44 (m, 1H), 6.95−6.87 (m, 2H), 6.79−6.76 (m, 1H), 4.80 (q, J = 6.4
Hz, 1H), 3.47−3.43 (m, 2H), 3.33 (d, J = 8.8 Hz, 1H), 2.87 (ddd, J =
14.0, 8.0, 3.2 Hz, 1H), 2.79 (d, J = 8.8 Hz, 1H), 2.07 (dt, J = 14.0, 10.0
Hz, 1H), 1.85−1.78 (m, 1H), 1.54−1.50 (m, 1H), 1.13 (d, J = 6.8 Hz,
Compound 26e. General procedure B; 51 mg, 88% yield; white
−1
solid, mp = 156 °C. IR (neat) cm : 2978, 2943, 2929, 1773, 1706,
1
1
5
(
1
3
1
2
2
651, 1588, 1447, 1403, 1081, 1036. H NMR (400 MHz, C D ) δ:
6 6
3
H). 13C NMR (100 MHz, C D ) δ: 172.2, 161.3, 158.6, 153.4, 132.0,
.12 (s, 1H), 4.91 (q, J = 6.4 Hz, 1H), 3.63−3.57 (m, 1H), 3.54−3.48
6 6
1
2
23.7, 122.7, 116.8, 115.9, 107.5, 102.9, 79.4, 68.4, 45.0, 38.3, 35.4,
m, 1H), 3.27 (d, J = 8.8 Hz, 1H), 2.80−2.73 (m, 2H), 2.04 (dt, J =
+
+
3.7, 20.5. HRMS (TOF, CI ) m/z: calcd for C H O [M + H]
4.0, 9.6 Hz, 1H), 1.85−1.76 (m, 1H), 1.55−1.51 (m, 1H), 1.44 (s,
18 17 6
H), 1.11 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, C D ) δ: 172.4,
329.1025, found 329.1033.
6
6
Compound 26k. General procedure B; 33 mg, 79% yield; colorless
63.4, 163.0, 161.8, 107.0, 100.2, 99.4, 79.2, 68.3, 45.0, 37.7, 35.4, 23.7,
−1
1
+
+
oil. IR (neat) cm : 2945, 2893, 1651, 1623, 1393, 1112, 1009. H
0.2, 19.2. HRMS (TOF, CI ) m/z: calcd for C H O [M + H]
15
17
6
NMR (400 MHz, CDCl ) δ: 4.12−4.07 (m, 1H), 4.02−3.97 (m, 1H),
3
93.1025, found 293.1021.
Compound 26f. General procedure B; 39 mg, 75% yield; colorless
2
.41−2.33 (m, 6H), 2.19−2.13 (m, 2H), 1.99−1.91 (m, 4H), 1.87−
13
−1
1.80 (m, 2H). C NMR (100 MHz, CDCl ) δ: 198.2, 169.4, 111.4,
108.5, 68.9, 36.7 (2C), 29.4, 28.8, 23.8, 20.9, 16.1. HRMS (TOF, CI )
m/z: calcd for C H O [M] 208.1099, found 208.1098.
3
oil. IR (neat) cm : 2954, 2927, 2855, 1712, 1632, 1611, 1576, 1398,
+
1
1
7
4
2
1
6
175, 1047. H NMR (400 MHz, CDCl ) δ: 7.73 (d, J = 7.6 Hz, 1H),
3
+
12
16
3
.49 (t, J = 8.0 Hz, 1H), 7.31−7.23 (m, 2H), 4.19−4.13 (m, 1H),
Compound 26l (Separable Diastereomers). General procedure B;
34 mg, 65% yield, dr 1:1. Diastereomer A: light-yellow solid, mp = 114
.10−4.04 (m, 1H), 2.75−2.70 (m, 2H), 2.42−2.37 (m, 2H), 2.17−
1
3
.08 (m, 3H), 2.04−1.98 (m, 1H). C NMR (100 MHz, CDCl ) δ:
3
−1
1
°
C. IR (neat) cm : 2955, 2893, 1742, 1630, 1389, 1055, 1010. H
NMR (400 MHz, C ) δ: 3.66−3.60 (m, 1H), 3.48−3.42 (m, 1H),
3.11−3.04 (m, 1H), 2.78−2.64 (m, 2H), 2.23−2.10 (m, 4H), 2.00−
63.1, 158.3, 152.7, 131.4, 123.8, 122.3, 116.6, 116.0, 109.3, 101.3,
9.2, 36.9, 29.0, 23.9, 17.8. HRMS (TOF, CI ) m/z: calcd for
C H O [M + H] 259.0970, found 259.0977.
+
D
6 6
+
1
5
15
4
13
1
(
3
.85 (m, 5H), 1.73−1.66 (m, 1H), 1.44−1.37 (m, 3H). C NMR
100 MHz, C D ) δ: 214.6, 195.9, 165.7, 114.0, 106.3, 69.5, 47.3, 37.8,
6.9, 34.9, 31.4, 28.2, 27.4, 22.9, 20.6. HRMS (TOF, CI ) m/z: calcd
for C H O [M + H] 263.1283, found 263.1289. Diastereomer B:
Compound 26g (Separable Diastereomers). General procedure B;
6 mg, 74% yield, dr 1.9:1. Major diastereomer: light-yellow solid, mp
6
6
4
=
1
6
1
1
+
−1
152 °C. IR (neat) cm : 2959, 2923, 2897, 1743, 1710, 1634, 1393,
+
1
15 19
4
053. H NMR (400 MHz, C D ) δ: 7.49 (d, J = 7.6 Hz, 1H), 7.00−
−1
6
6
light-yellow solid, mp = 118 °C. IR (neat) cm : 2947, 2893, 1741,
.93 (m, 2H), 6.84−6.81 (m, 1H), 3.52−3.47 (m, 1H), 3.43−3.38 (m,
H), 3.03−2.96 (m, 1H), 2.81−2.68 (m, 2H), 2.14−1.92 (m, 4H),
1
1
2
1
1
1
1
2
2
647, 1615, 1385, 1072. H NMR (400 MHz, C D ) δ: 3.64−3.60 (m,
6
6
H), 3.50 (q, J = 8.0 Hz, 1H), 2.66−2.60 (m, 1H), 2.57−2.52 (m,
H), 2.17 (dt, J = 16.8, 4.0 Hz, 1H), 2.08 (d, J = 8.0 Hz, 1H), 2.03−
.95 (m, 1H), 1.91−1.83 (m, 6H), 1.72−1.66 (m, 1H), 1.54−1.46 (m,
13
.83−1.68 (m, 2H), 1.47−1.44 (m, 1H). C NMR (100 MHz, C D )
6
6
δ: 213.9, 161.4, 155.8, 153.3, 131.4, 123.5, 122.4, 116.8, 116.2, 107.4,
+
1
05.0, 70.0, 47.2, 37.9, 35.1, 33.0, 27.2, 23.1. HRMS (TOF, CI ) m/z:
calcd for C H O [M] 312.0998, found 312.0994. Minor
diastereomer: light-yellow solid, mp = 163 °C. IR (neat) cm :
956, 2921, 1743, 1709, 1626, 1390, 1075. H NMR (400 MHz,
13
H), 1.29−1.23 (m, 2H). C NMR (100 MHz, C D ) δ: 214.0, 196.0,
+
6
6
1
8
16
5
69.7, 113.7, 107.1, 67.5, 54.8, 37.3, 35.7, 35.3, 32.4, 29.0, 25.3, 23.9,
−1
0.3. HRMS (TOF, CI ) m/z: calcd for C H O [M + H]+
+
1
15 19
4
2
63.1283, found 263.1292.
Compound 26m (Inseparable Diastereomers). General procedure
B; 47 mg, 85% yield, dr 5:1; light-yellow solid, mp = 134−136 °C. IR
C D ) δ: 7.53 (d, J = 8.0 Hz, 1H), 6.95−6.89 (m, 2H), 6.80−6.76 (m,
6
6
1
2
1
H), 3.72−3.69 (m, 1H), 3.48−3.42 (m, 2H), 2.76−2.64 (m, 2H),
.08 (d, J = 8.0 Hz, 1H), 2.03−1.94 (m, 1H), 1.83−1.72 (m, 1H),
−1
(
neat) cm : 2946, 2878, 1741, 1656, 1631, 1387, 1073, 1045, 1008.
1
3
.66−1.58 (m, 3H), 1.52−1.47 (m, 1H). C NMR (100 MHz, C D )
1
6
6
Diastereomer A: H NMR (400 MHz, C D ) δ: 3.44−3.37 (m, 1H),
6
6
δ: 213.0, 160.9, 159.0, 153.4, 131.7, 123.6, 122.6, 116.6, 116.2, 108.2,
04.3, 67.8, 54.3, 35.7, 35.3, 33.6, 24.4, 23.8. HRMS (TOF, CI ) m/z:
calcd for C H O [M] 312.0998, found 312.1014.
3
2
.30−3.27 (m, 1H), 3.03−2.96 (m, 1H), 2.75−2.69 (m, 1H), 2.61−
+
1
.53 (m, 1H), 2.24−2.12 (m, 4H), 2.02−1.95 (m, 2H), 1.91−1.82 (m,
+
13
18
16
5
4H), 1.79−1.69 (m, 1H), 1.51−1.41 (m, 4H). C NMR (100 MHz,
Compound 26h (Inseparable Diastereomers). General procedure
B; 48 mg, 74% yield, dr 1.3:1; light-yellow solid, mp = 146−148 °C. IR
C D ) δ: 215.2, 196.3, 164.9, 115.0, 98.3, 62.1, 50.9, 38.2, 37.3, 31.5,
6
6
1
3
1.4, 28.0, 27.9, 24.4, 21.1, 18.3. Diastereomer B: H NMR (400 MHz,
−1
(
neat) cm : 2947, 2879, 1741, 1709, 1628, 1388, 1073, 1046, 1030.
C D ) δ: 3.58−3.55 (m, 1H), 3.44−3.37 (m, 1H), 3.30−3.27 (m, 1H),
6
6
1
Diastereomer A: H NMR (400 MHz, CDCl ) δ: 7.81−7.76 (m, 1H),
3
2.92−2.88 (m, 1H), 2.61−2.53 (m, 1H), 2.08−2.06 (m, 2H), 1.97−
13
7
3
1
.51−7.46 (m, 1H), 7.30−7.22 (m, 2H), 3.70−3.67 (m, 1H), 3.58−
.48 (m, 2H), 2.84−2.80 (m, 1H), 2.76−2.68 (m, 2H), 2.53−2.46 (m,
1
.95 (m, 4H), 1.79−1.69 (m, 3H), 1.41−1.25 (m, 6H). C NMR
(100 MHz, C D ) δ: 213.8, 196.0, 168.6, 114.6, 98.0, 62.1, 55.7, 37.4,
36.6, 32.0, 31.8, 28.6, 25.2, 24.5, 20.4, 18.2. HRMS (TOF, CI ) m/z:
6
6
13
+
H), 2.27−2.18 (m, 1H), 2.11−1.94 (m, 2H), 1.82−1.55 (m, 4H).
C
+
NMR (100 MHz, CDCl ) δ: 214.0, 161.7, 158.4, 152.8, 131.8, 124.1,
calcd for C H O [M] 276.1362, found 276.1357.
3
16 20
4
1
1
1
3
2
22.4, 116.6, 115.5, 104.4, 99.1, 62.7, 55.4, 36.8, 32.8, 31.3, 24.6, 23.5,
Compound 26n. General procedure B; 32 mg, 60% yield; light-
1
−1
8.1. Diastereomer B: H NMR (400 MHz, CDCl ) δ: 7.81−7.76 (m,
yellow solid, mp = 152 °C. IR (neat) cm : 2925, 2854, 1776, 1623,
3
1
H), 7.51−7.46 (m, 1H), 7.30−7.22 (m, 2H), 3.58−3.48 (m, 2H),
.30−3.23 (m, 1H), 2.76−2.68 (m, 1H), 2.40−2.33 (m, 2H), 2.27−
1389, 1191, 1072, 924. H NMR (400 MHz, C D ) δ: 4.45 (d, J = 9.6
6
6
Hz, 1H), 3.93 (dd, J = 9.2, 5.6 Hz, 1H), 3.62−3.56 (m, 1H), 3.48−
3.39 (m, 2H), 2.71 (ddd, J = 14.0, 8.0, 3.6 Hz, 1H), 2.17 (d, J = 8.4 Hz,
1H), 2.09−1.93 (m, 2H), 1.84−1.72 (m, 4H), 1.46−1.40 (m, 1H),
13
.18 (m, 1H), 2.11−1.94 (m, 3H), 1.82−1.55 (m, 4H). C NMR
(
1
100 MHz, CDCl ) δ: 215.7, 162.3, 155.5, 152.7, 131.6, 124.1, 122.3,
3
13
16.7, 115.5, 104.9, 99.2, 62.7, 50.7, 38.1, 32.2, 31.0, 27.2, 24.1, 18.3.
1.18−1.13 (m, 2H). C NMR (100 MHz, C D ) δ: 196.2, 173.4,
6
6
J
dx.doi.org/10.1021/jo501604e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
70.1, 111.9, 106.1, 71.4, 68.2, 46.3, 36.7, 35.3, 32.0, 28.7, 23.9, 19.9.
109.3, 77.3, 68.5, 44.4, 36.3, 35.4, 33.3, 26.4, 23.7, 19.7. HRMS (TOF,
+
+
+
+
HRMS (TOF, CI ) m/z: calcd for C H O [M + H] 265.1076,
CI ) m/z: calcd for C H O [M] 264.0998, found 264.1000. The
14
17
5
14 16 5
found 265.1077.
Compound 26o. General procedure B; 39 mg, 70% yield; white
solid, mp = 154 °C. IR (neat) cm : 2947, 2895, 1774, 1627, 1390,
structure of 26t (CCDC 1013975) was confirmed by single-crystal X-
ray diffraction analysis.
−1
1
1
1
1
1
163, 1032, 1002. H NMR (400 MHz, C D ) δ: 4.68 (q, J = 6.4 Hz,
ASSOCIATED CONTENT
6
6
■
H), 3.64−3.59 (m, 1H), 3.49 (q, J = 7.6 Hz, 1H), 3.25 (d, J = 8.8 Hz,
*
S
Supporting Information
H), 2.79−2.72 (m, 2H), 2.11−2.02 (m, 2H), 1.89−1.74 (m, 4H),
1
13
13
Copies of H and C NMR spectra of new compounds and X-
ray data (CIF) for compounds 11b, 11e, 11h, 11l, 11p, 26b-1,
26d, and 26t. This material is available free of charge via the
Internet at http://pubs.acs.org. The supplementary crystallo-
graphic data have also been deposited at the Cambridge
Crystallographic Data Centre (http://www.ccdc.cam.ac.uk)
under the following entry numbers: 11b (CCDC 1013961),
.52−1.46 (m, 1H), 1.20−1.16 (m, 5H). C NMR (100 MHz, C D )
6
6
δ: 196.4, 172.9, 169.4, 112.9, 106.4, 80.6, 68.2, 45.2, 37.2, 36.7, 35.4,
+
2
+
8.7, 23.8, 20.3, 20.0. HRMS (TOF, CI ) m/z: calcd for C H O [M
H] 279.1232, found 279.1226.
Compound 26p. General procedure B; 32 mg, 83% yield; light-
yellow oil. IR (neat) cm : 2956, 2923, 2852, 1688, 1621, 1404, 1087.
H NMR (400 MHz, C D ) δ: 3.83−3.78 (m, 1H), 3.60−3.54 (m,
15 19 5
+
−1
1
6
6
1
1
1
1
H), 2.48−2.40 (m, 1H), 2.29−2.25 (m, 1H), 2.05−2.03 (m, 2H),
.96−1.95 (m, 2H), 1.81−1.73 (m, 2H), 1.55−1.49 (m, 1H), 1.38−
.34 (m, 3H). 13C NMR (100 MHz, C D ) δ: 201.5, 181.3, 115.0,
11e (CCDC 1013962), 11h (CCDC 1013963), 11l (CCDC
1013964), 11p (CCDC 1013966), 26b-1 (CCDC 1013972),
26d (CCDC 1013967), and 26t (CCDC 1013975).
6
6
+
11.0, 68.8, 36.7, 33.4, 29.2, 26.5, 23.8, 15.3. HRMS (TOF, CI ) m/z:
+
calcd for C H O [M + H] 195.1021, found 195.1029.
11
15
3
AUTHOR INFORMATION
Corresponding Author
*E-mail: rtong@ust.hk
Compound 26q (Separable Diastereomers). General procedure B;
■
3
°
1
7
1
1
1
0 mg, 60% yield, dr 1:0.8. Major diastereomer: white solid, mp = 178
−1
C. IR (neat) cm : 2955, 2922, 2852, 1740, 1690, 1625, 1399, 1073,
1
012. H NMR (400 MHz, C D ) δ: 3.67−3.61 (m, 1H), 3.50 (q, J =
6
6
Notes
.6 Hz, 1H), 3.37−3.34 (m, 1H), 2.91−2.85 (m, 1H), 2.76−2.70 (m,
H), 2.00−1.94 (m, 1H), 1.91−1.89 (m, 3H), 1.83−1.78 (m, 5H),
The authors declare no competing financial interest.
13
.50−1.43 (m, 2H). C NMR (100 MHz, C D ) δ: 212.9, 201.6,
6
6
ACKNOWLEDGMENTS
■
82.8, 114.7, 110.0, 67.7, 54.2, 35.3, 35.1, 33.5, 31.5, 26.3, 23.8, 22.2.
+
+
This research was financially supported by The Hong Kong
University of Science and Technology (HKUST) and the
Research Grant Council of Hong Kong (ECS 605912, GRF
605113, and GRF 16305314). The authors are also grateful to
Prof. Dr. Ian Williams (HKUST) and Dr. Herman Sung
HRMS (TOF, CI ) m/z: calcd for C H O [M + H] 249.1127,
14
17
4
found 249.1133. Minor diastereomer: white solid, mp = 130 °C. IR
−1
1
(
neat) cm : 2958, 2923, 1741, 1692, 1640, 1402, 1056, 1015. H
NMR (400 MHz, C D ) δ: 3.64−3.58 (m, 1H), 3.43 (q, J = 7.6 Hz,
6
6
1
2
1
1
H), 2.80−2.65 (m, 2H), 2.47−2.40 (m, 1H), 2.11−2.04 (m, 1H),
.01−1.97 (m, 3H), 1.94−1.86 (m, 3H), 1.80−1.66 (m, 2H), 1.45−
.36 (m, 2H). 13C NMR (100 MHz, C D ) δ: 214.0, 201.9, 179.3,
(
HKUST) for the single-crystal X-ray diffraction analyses.
6
6
17.6, 109.7, 70.1, 46.8, 38.3, 35.1, 33.2, 31.0, 26.9, 26.5, 22.9. HRMS
REFERENCES
+
+
(
TOF, CI ) m/z: calcd for C H O [M + H] 249.1127, found
■
14
17
4
(
1) (a) Fairlamb, I. J. S.; Marrison, L. R.; Dickinson, J. M.; Lu, F.-J.;
2
49.1137.
Compound 26r (Inseparable Diastereomers). General procedure
B; 47 mg, 90% yield, dr 1.2:1; yellow solid, mp = 156−158 °C. IR
Schmidt, J. P. Bioorg. Med. Chem. 2004, 12, 4285. (b) McGlacken, G.
P.; Fairlamb, I. J. S. Nat. Prod. Rep. 2005, 22, 369.
(2) (a) Hagen, S.; Vara Prasad, J. V. N.; Tait, B. D. Adv. Med. Chem.
−1
(
neat) cm : 2948, 2881, 1740, 1694, 1643, 1400, 1123, 1093, 1070,
1
2
000, 5, 159. (b) Yu, D.; Suzuki, M.; Xie, L.; Morris-Natschke, S. L.;
Lee, K.-H. Med. Res. Rev. 2003, 23, 322.
3) (a) Otoguro, K.; Kuno, F.; Omura, S. Pharmacol. Ther. 1997, 76,
5. (b) Peng, F.-C. J. Nat. Prod. 1995, 58, 857. (c) Obata, R.;
Sunazuka, T.; Tian, Z.; Tomoda, H.; Harigaya, Y.; Omura, S.; Smith,
1
1
2
1
2
2
3
2
2
045. Diastereomer A: H NMR (400 MHz, CDCl ) δ: 3.71−3.64 (m,
3
H), 3.59−3.55 (m, 1H), 3.02−2.95 (m, 1H), 2.61−2.59 (m, 2H),
.49−2.39 (m, 4H), 2.35−2.30 (m, 1H), 2.21−2.05 (m, 4H), 1.84−
(
̅
13
4
.79 (m, 2H), 1.59−1.52 (m, 2H). C NMR (100 MHz, CDCl ) δ:
3
16.1, 204.0, 180.1, 117.7, 102.0, 62.6, 50.5, 38.6, 33.4, 31.0, 30.7, 26.9,
6.5, 24.1, 17.9. Diastereomer B: H NMR (400 MHz, CDCl ) δ:
̅
1
A. B., III. Chem. Lett. 1997, 935. For leading total syntheses of
arisugacins, see: (d) Cole, K. P.; Hsung, R. P. Tetrahedron Lett. 2002,
3
.71−3.64 (m, 2H), 3.36 (t, J = 6.4 Hz, 1H), 2.79−2.75 (m, 1H),
4
3, 8791. (e) Sunazuka, T.; Handa, M.; Nagai, K.; Shirahata, T.;
Harigaya, Y.; Otoguro, K.; Kuwajima, I.; Omura, S. Org. Lett. 2002, 4,
367.
.72−2.67 (m, 1H), 2.53−2.49 (m, 2H), 2.47−2.39 (m, 4H), 2.21−
.05 (m, 1H), 1.94−1.89 (m, 2H), 1.72−1.68 (m, 4H). C NMR
13
̅
(
100 MHz, CDCl ) δ: 214.3, 203.7, 183.5, 115.6, 101.4, 62.7, 55.3,
3
+
3
6.3, 33.7, 31.3, 30.8, 26.2, 24.8, 21.5, 17.6. HRMS (TOF, CI ) m/z:
(4) For recent reviews, see: (a) Goel, A.; Ram, V. J. Tetrahedron
2009, 65, 7865. (b) Burns, M. J.; Ronson, T. O.; Taylor, R. J. K.;
Fairlamb, I. J. S. Beilstein J. Org. Chem. 2014, 10, 1159.
(5) Trisuwan, K.; Rukachaisirikul, V.; Sukpondma, Y.; Phongpaichit,
S.; Preedanon, S.; Sakayaroj, J. Chem. Pharm. Bull. 2009, 57, 1100.
(6) Asai, T.; Chung, Y.-M.; Sakurai, H.; Ozeki, T.; Chang, F.-R.;
Yamashita, K.; Oshima, Y. Org. Lett. 2012, 14, 513.
(7) Song, L.; Yao, H.; Zhu, L.; Tong, R. Org. Lett. 2013, 15, 6.
(8) For selected references, see: (a) Ikawa, M.; Stahmann, M. A.;
Link, K. P. J. Am. Chem. Soc. 1944, 66, 902. (b) Seidman, M.;
Robertson, D. N.; Link, K. P. J. Am. Chem. Soc. 1950, 72, 5193.
(c) Seidman, M.; Link, K. P. J. Am. Chem. Soc. 1952, 74, 1885. (d) de
+
calcd for C H O [M + H] 263.1283, found 263.1284.
15
19
4
Compound 26s. General procedure B; 37 mg, 73% yield; white
−1
solid, mp = 189 °C. IR (neat) cm : 2956, 2924, 2854, 1775, 1691,
1
1
4
1
8
1
2
2
2
630, 1401, 1198, 1152, 1024, 989. H NMR (400 MHz, C D ) δ:
6 6
.74 (d, J = 8.8 Hz, 1H), 3.66 (dd, J = 9.2, 5.2 Hz, 1H), 3.62−3.56 (m,
H), 3.44 (q, J = 8.0 Hz, 1H), 3.12−3.09 (m, 1H), 2.74 (ddd, J = 14.0,
.0, 3.6 Hz, 1H), 2.01 (d, J = 8.0 Hz, 1H), 2.00−1.95 (m, 1H), 1.79−
13
.67 (m, 5H), 1.44−1.41 (m, 1H). C NMR (100 MHz, C D ) δ:
6
6
01.5, 183.1, 172.8, 112.8, 109.1, 68.6, 68.4, 45.6, 35.3, 33.3, 31.3, 26.3,
+
+
3.8. HRMS (TOF, CI ) m/z: calcd for C H O [M + H]
51.0919, found 251.0925.
Compound 26t. General procedure B; 48 mg, 90% yield; light-
yellow solid, mp = 154 °C. IR (neat) cm : 2980, 2931, 1774, 1692,
635, 1401, 1211, 1149, 1085. H NMR (400 MHz, C D ) δ: 5.06 (q,
1
3
15
5
March, P.; Moreno-Manas
Chem. 1984, 21, 1369. (e) de March, P.; Moreno-Manas
̃
, M.; Pleixats, R.; Roca, J. L. J. Heterocycl.
−1
̃
, M.; Casado,
1
1
J.; Pleixats, R.; Roca, J. L.; Trius, A. J. Heterocycl. Chem. 1984, 21, 85.
(f) Shen, H. C.; Wang, J.; Cole, K. P.; McLaughlin, M. J.; Morgan, C.
D.; Douglas, C. J.; Hsung, R. P.; Coverdale, H. A.; Gerasyuto, A. I.;
Hahn, J. M.; Liu, J.; Wei, L.-L.; Sklenicka, H. M.; Zehnder, L. R.;
Zificsak, C. A. J. Org. Chem. 2003, 68, 1729. This cascade Knoevenagel
6
6
J = 6.4 Hz, 1H), 3.66−3.60 (m, 1H), 3.49 (q, J = 8.0 Hz, 1H), 3.03 (d,
J = 7.2 Hz, 1H), 2.80−2.74 (m, 1H), 2.66 (d, J = 8.0 Hz, 1H), 2.08−
2
.00 (m, 1H), 1.83−1.74 (m, 5H), 1.49−1.47 (m, 1H), 0.98 (d, J = 6.4
13
Hz, 3H). C NMR (100 MHz, C D ) δ: 201.7, 182.6, 172.4, 113.6,
6
6
K
dx.doi.org/10.1021/jo501604e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
condensation/six-π-electron electrocyclization sequence constitutes a
formal [3 + 3] cycloaddition strategy to construct 1-oxadecalins and
has been fully exploited in many elegant total syntheses. For recent
reviews, see: (g) Deng, J.; Wang, X.-N.; Hsung, R. P. A Formal [3 + 3]
Cycloaddition Approach to Natural Product Synthesis. In Methods and
Applications of Cycloaddition Reactions in Organic Syntheses; Nishiwaki,
N., Ed.; Wiley-VCH: Weinheim, Germany, 2014. (h) Hsung, R. P.;
Kurdyumov, A. V.; Sydorenko, N. Eur. J. Org. Chem. 2005, 23.
(c) Sreedharan, D. T.; Clive, D. L. J. Org. Biomol. Chem. 2013, 11,
3128. (d) Saitman, A.; Sullivan, S. D. E.; Theodorakis, E. A.
Tetrahedron Lett. 2013, 54, 1612.
(19) Batt, F.; Fache, F. Eur. J. Org. Chem. 2011, 6039.
(20) Wilson, N. S.; Keay, B. A. J. Org. Chem. 1996, 61, 2918.
(21) Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165.
(22) Appendino, G.; Cravotto, G.; Toma, L.; Annunziata, R.;
Palmisano, G. J. Org. Chem. 1994, 59, 5556.
(23) Patterson, J. W., Jr.; Reusch, W. Synthesis 1971, 155.
(24) Krause, M.; Hoffmann, H. M. R. Synlett 1990, 485.
(25) Bunnelle, W. H.; Meyer, L. A. J. Org. Chem. 1988, 53, 4038.
̀
(26) Lifchits, O.; Mahlau, M.; Reisinger, C. M.; Lee, A.; Fares, C.;
Polyak, I.; Gopakumar, G.; Thiel, W.; List, B. J. Am. Chem. Soc. 2013,
(
9) For selected examples, see: (a) Bonne, D.; Coquerel, Y.;
Constantieux, T.; Rodriguez, J. Tetrahedron: Asymmetry 2010, 21,
1085. (b) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem.
2
004, 4957. (c) Wang, G.-W.; Gao, J. Org. Lett. 2009, 11, 2385.
(
10) For recent reviews covering enantioselective conjugate
additions, see: (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56,
033. (b) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171. For
135, 6677.
8
̈
(27) Cormier, R. A.; Schreiber, W. L.; Agosta, W. C. J. Am. Chem. Soc.
1973, 95, 4873.
recent examples covering asymmetric Michael addition of cyclic 1,3-
dicarbonyl compounds to α,β-unsaturated ketones, see: (c) Halland,
N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 4955.
(
5
d) Halland, N.; Velgaard, T.; Jørgensen, K. A. J. Org. Chem. 2003, 68,
067. (e) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.-G.;
Chen, Y.-C. Org. Lett. 2007, 9, 413. (f) Chen, X.-K.; Zheng, C.-W.;
Zhao, S.-L.; Chai, Z.; Yang, Y.-Q.; Zhao, G.; Cao, W.-G. Adv. Synth.
Catal. 2010, 352, 1648. (g) Calter, M. A.; Wang, J. Org. Lett. 2009, 11,
2
5
205. (h) Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006, 8,
239. (i) Kristensen, T. E.; Vestli, K.; Hansen, F. K.; Hansen, T. Eur. J.
Org. Chem. 2009, 5185. (j) Dong, Z.; Wang, L.; Chen, X.; Liu, X.; Lin,
L.; Feng, X. Eur. J. Org. Chem. 2009, 5192. (k) Zhu, X.; Lin, A.; Shi, Y.;
Guo, J.; Zhu, C.; Cheng, Y. Org. Lett. 2011, 13, 4382. For other
conjugate additions, see: (l) Ivanov, I. C.; Manolov, I.; Alexandrova, L.
A. Arch. Pharm. 1990, 521. (m) Talapatra, S. K.; Chakrabarti, R.;
Mukhopadhyay, P. K.; Das, P. K.; Talapatra, B. Heterocycles 1984, 22,
5
(
2
19.
11) (a) Rueping, M.; Merino, E.; Sugiono, E. Adv. Synth. Catal.
008, 350, 2127. (b) Rueping, M.; Sugiono, E.; Merino, E. Angew.
Chem., Int. Ed. 2008, 47, 3046. (c) Rueping, M.; Sugiono, E.; Merino,
E. Chem.Eur. J. 2008, 14, 6329. (d) Franke, P. T.; Richter, B.;
Jørgensen, K. A. Chem.Eur. J. 2008, 14, 6317. (e) Rueping, M.;
Merino, E.; Bolte, M. Org. Biomol. Chem. 2012, 10, 6201. (f) Rueping,
M.; Merino, E.; Sugiono, E. ChemCatChem 2012, 4, 987. (g) Volla, C.
M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390.
(
12) For a recent review, see: Kitson, R. R. A.; Millemaggi, A.; Taylor,
R. J. K. Angew. Chem., Int. Ed. 2009, 48, 9426.
13) (a) Erkkila, A.; Pihko, P. M. J. Org. Chem. 2006, 71, 2538.
b) Erkkila, A.; Pihko, P. M. Eur. J. Org. Chem. 2007, 4205.
c) Benohoud, M.; Erkkila, A.; Pihko, P. M. Org. Synth. 2010, 87, 201.
14) For examples of Lewis acid-catalyzed enantioselective Michael
(
̈
(
(
̈
̈
(
additions of 1,3-dicarbonyls to acyclic substrates, see: (a) Hamashima,
Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240.
(
4
b) End, N.; Macko, L.; Zehnder, M.; Pfaltz, A. Chem.Eur. J. 1998,
, 818. (c) Ji, J.; Barnes, D. M.; Zhang, J.; King, S. A.; Wittenberger, S.
J.; Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215. (d) Barnes, D.
M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.; Morton, H. E.;
Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S. J.; Zhang, J.
J. Am. Chem. Soc. 2002, 124, 13097.
(
15) (a) Pettigrew, J. D.; Wilson, P. D. J. Org. Chem. 2006, 71, 1620.
The key step in total syntheses of xyloketals by Krohn and co-workers
may involve the same oxonium ion intermediate. See: (b) Krohn, K.;
Riaz, M.; Flo
M. Tetrahedron Lett. 2004, 45, 293.
16) For leading references, see: (a) Casadei, M. A.; Galli, C.;
̈
rke, U. Eur. J. Org. Chem. 2004, 1261. (c) Krohn, K.; Riaz,
(
Mandolini, L. J. Am. Chem. Soc. 1984, 106, 1051. (b) Galli, C.;
Illuminati, G.; Mandolini, L.; Tamborra, P. J. Am. Chem. Soc. 1977, 99,
2591. (c) Illuminati, G.; Mandolini, L.; Masci, B. J. Am. Chem. Soc.
1
975, 97, 4960.
(
17) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(
18) A similar sequence has been widely used in synthesis of other α-
functionalized butenolides. For recent references, see: (a) Weinstabl,
H.; Gaich, T.; Mulzer, J. Org. Lett. 2012, 14, 2834. (b) Himmelbauer,
M.; Farcet, J.-B.; Gagnepain, J.; Mulzer, J. Org. Lett. 2013, 15, 3098.
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dx.doi.org/10.1021/jo501604e | J. Org. Chem. XXXX, XXX, XXX−XXX