Diels-Alder Reactions of γ-Hydroxybutenolides: Approach to the Himbacine Tricyclic Core

Article abstract of DOI:10.1055/s-0035-1561348

The Diels-Alder reaction of γ-hydroxybutenolides with dienes gave good yields of cycloadducts under thermal and Lewis acid catalyzed conditions. The application of this methodology to a more complex system was demonstrated by the synthesis of a model system for the tricyclic himbacine core. The stereo- and regioselective Diels-Alder reaction established three of the stereogenic centers, with the fourth stereogenic center secured by diastereoselective alkylation of the cycloadduct.

Full text of DOI:10.1055/s-0035-1561348

SYNTHESIS
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0
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, 924–934
paper
924
W. H. Miles et al.
Paper
Synthesis
Diels–Alder Reactions of γ-Hydroxybutenolides: Approach to the
Himbacine Tricyclic Core
William H. Miles*a
Dasan M. Thamattoorb
Ryan E. Cerbonea
Daniel J. Beidemana
Samantha M. Zeidersa
Natalie E. Jasiewicza
Stephanie M. Petersena
Barbara J. Naimolia
Joseph V. Leoa
R2
R2
R1
O
R3
R4
R3
R4
CO2H
COR1
D
O
+
OH
(or Lewis acid
catalyzed)
R5
R5
ring-chain
tautomerism
- 42–99% yield
- 22 examples
OH
- stereo- and regioselectivity up to
95:5 dictated by COR1 group
R1
O
Ida B. G. Suarsanaa
Jason S. Georgea
Nicholas J. Albanoa
O
R1 = H, alkyl
a Department of Chemistry, Lafayette College, Easton, PA 18042, USA
milesw@lafayette.edu
b Department of Chemistry, Colby College, Waterville, ME 04901, USA
Received: 19.11.2015
Accepted after revision: 10.01.2016
Published online: 02.02.2016
tions of γ-hydroxybutenolides, including the Diels–Alder
reaction, suggests that the rate of interconversion between
the ring and chain tautomer is relatively fast on the labora-
tory timescale.6 The reactive tautomer taut-1 is a substitut-
ed acrylic acid, a functional group that possesses some
challenges in its use as a dienophile, but several studies
have shown that acrylic acids can be employed in stereose-
lective and regioselective Diels–Alder reactions.2a,7
DOI: 10.1055/s-0035-1561348; Art ID: ss-2015-m0671-op
Abstract The Diels–Alder reaction of γ-hydroxybutenolides with
dienes gave good yields of cycloadducts under thermal and Lewis acid
catalyzed conditions. The application of this methodology to a more
complex system was demonstrated by the synthesis of a model system
for the tricyclic himbacine core. The stereo- and regioselective Diels–
Alder reaction established three of the stereogenic centers, with the
fourth stereogenic center secured by diastereoselective alkylation of
the cycloadduct.
OH
R1
O
R1
O
O
O
Key words γ-hydroxybutenolide, Diels–Alder reaction, himbacine,
OH
Lewis acid catalysis, isomerization
taut-1
1
Scheme 1 Tautomerism of γ-hydroxybutenolides
The Diels–Alder reaction is a powerful method for the
stereoselective synthesis of cyclic compounds.1 Alkenes
possessing two electron-withdrawing groups are attractive
dienophiles, but selectivity, both stereochemical and re-
giochemical, becomes an issue for many of these reactive
alkenes.2 In some cases, stereochemical selectivity for the
reaction of these dienophiles is markedly improved with
the use of Lewis acid catalysis.2a,3
At first inspection, γ-hydroxybutenolides 1 would not
appear to be ideal dienophiles since they resemble substi-
tuted γ-lactones,4 which usually require more forcing con-
ditions for the Diels–Alder reaction compared to dieno-
philes with two electron-withdrawing groups (Scheme 1).
The representation of the ring tautomer belies the reactivi-
ty of γ-hydroxybutenolides since there is interconversion to
the chain tautomer (taut-1), which is also present in signifi-
cant quantities at equilibrium.5 In addition, several reac-
The reaction of γ-hydroxybutenolides as dienophiles in
the Diels–Alder reaction is limited to the reactions of the
parent system 1e (R1 = H) with cyclopentadienes8 and two
other special cases.9 Given the ready availability of γ-hy-
droxybutenolides 1 from several methods (photooxidation
of substituted 2-silylfurans10a,b and 2-furaldehydes,10c,d and
perchlorate oxidation of 2-substituted furans10e), we under-
took a systematic study of their potential as dienophiles in
the Diels–Alder reaction. In particular, we were interested
in developing conditions that would lead to high regio- and
stereoselectivity in the Diels–Alder reaction. Further, we
were interested in investigating their potential in address-
ing the challenges of synthesizing the himbacine tricyclic
core, a topic of continued interest.11
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 924–934

925
W. H. Miles et al.
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Synthesis
The thermal Diels–Alder reaction of several γ-hydroxy-
butenolides 1 with cyclopentadiene, 1,3-cyclohexadiene,
2,3-dimethyl-1,3-butadiene, isoprene, and (E)-3-methyl-1-
phenyl-1,3-butadiene12 (Scheme 2) are summarized in Ta-
ble 1. γ-Hydroxybutenolides 1a–e were readily prepared ei-
ther by the photolysis of the corresponding trimethylsilyl-
furan, in the case of 1a–c10a,b [acetone (1% H2O); polymer-
supported rose bengal; 200 W flood lamps; 0 °C], or the
photolysis of the corresponding furaldehyde, in the case of
1d10d and 1e10c (MeOH; rose bengal; 200 W flood lamps; 0–
25 °C; 1e is also available by photolysis of 2-trimethylsilyl-
furan and is a commercial product) according to literature
procedures. They were good dienophiles, reacting with cy-
clopentadiene to give Diels–Adler adducts in high yields
and endo-selectivity at room temperature (Table 1, entries
1, 6, 11, 15, and 18). The less reactive 1,3-cyclohexadiene
required more forcing conditions (entries 2, 7, 12, and 19),
leading to some isomerization of γ-hydroxybutenolides 1b
and 1c to the corresponding (E)-β-acylacrylic acids, which
then reacted to give trans-products. 2,3-Dimethyl-1,3-buta-
diene reacted with 1a–e (entries 3, 8, 13, 16, and 20) with-
out isomerization and in good yields. The use of isoprene as
a diene probed the issue of regiochemistry (entries 4, 9, and
14); there was little or no selectivity for the formation of
10, in which the acyl group acted as a ‘para’-directing group
relative to the methyl substituent of isoprene. The reaction
of 1a, 1b, and 1d with (E)-3-methyl-1-phenyl-1,3-butadi-
ene gave diastereomer 11 with approximately 90–95%
regio- and diastereoselectivity, the consequence of endo-
selectivity and the acyl group acting as a strong ‘ortho/para’-
directing group (entries 5, 10, and 17).
carboxylic acid and no significant formation of the corre-
sponding ring tautomer, the ring tautomer for the Diels–
Alder products of γ-hydroxybutenolides 1 with dienes was
evident, particularly in the case of bicyclic compounds and
cycloadducts of 1e. For bicyclic compounds 3 and 4, the ring
tautomers 5/7 and 6/8 were the major tautomeric species.
For cycloadducts 9–11 derived from 1a–d, however, there
was very little evidence for significant amounts of the ring
tautomer. In order to reduce the complexity of the NMR
spectra, DABCO was added to catalyze the tautomerization
process, leading to fast exchange and averaged spectra of
the chain tautomer and the two diastereomeric ring tau-
tomers. We have previously shown that the amine-cata-
lyzed tautomerization of γ-hydroxybutenolides facilitates
the identification of epimeric γ-hydroxybutenolides.13,14
The assignment of the regiochemistry for the isoprene cy-
cloadducts was determined by the isomerization (NaOH in
MeOH) of 10a to the known trans-isomer of 10a;2a,7a the as-
signment of regiochemistry for 10b and 10c was based on
1
the similarity of common features observed in the H and
13C NMR spectra for these compounds. The assignment of
regiochemistry for cycloadducts 11 was based on a strong
NOE enhancement observed for the ortho-protons of the
phenyl ring when the alkenyl proton at δ = 5.4 was irradiat-
ed. The magnitudes for the coupling constants observed for
11 are best explained by a conformation in which the phe-
nyl and carboxylic acid groups occupy a pseudo-equatorial
position and the acyl group is pseudo-axial.
In order to increase the reaction rate and improve the
regio- and stereoselectivity for the Diels–Alder reactions of
1, we looked at a variety of Lewis acid catalyzed conditions,
with some of the results summarized in Table 2. The two
catalyst systems that worked best for the catalyzed Diels–
Alder reaction of 1 were DIPEA/SnCl4 and Sc(OTf)3. In our
previous studies of the Diels–Alder reactions of (E)-β-acyl-
acrylic acids,2a we found that deprotonation of the acrylic
The identification of the Diels–Alder products by NMR
spectroscopy was complicated by the tautomerization pro-
cess of the cycloadducts. Unlike the Diels–Alder products of
the reaction of (E)-β-acylacrylic acids with dienes in which
there is a trans-relationship between the acyl group and
n
n
n
OH
n
R1
O
O
O
CO2H
COR1
3 (n = 1)
4 (n = 2)
O
O
R1
O
R1
1
HO
OH
5 (n = 1)
6 (n = 2)
7 (n = 1)
8 (n = 2)
COR1
CO2H
CO2H
COR1
CO2H
COR1
R2
R2 = H, Ph
a: R1 = Me
R2
R2
9
b: R1 = (CH2)4Me
c: R1 = CH2CH2Ph
d: R1 = CH2OAc
e: R1 = H
iso-10 (R2 = H)
iso-11 (R2 = Ph)
10 (R2 = H)
11 (R2 = Ph)
Scheme 2 Thermal Diels–Alder reaction of 1
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W. H. Miles et al.
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Synthesis
Table 1 Thermal Diels–Alder Reaction of γ-Hydroxybutenolides 1 with Dienes
OH
Δ
R1
O
diene
+
3, 4, 9–11
O
1
Entry
R1
Me (1a)
Diene
cyclopentadiene
Solvent; temp; time
Product
Yield (%); dra
1
2
CH2Cl2; 22 °C; 1 h
3a
4a
99; >96:4
74; >96:4
94
Me
1,3-cyclohexadiene
(CH2=CMe)2
toluene; 110 °C; 20 h
CH2Cl2; 22 °C; 96 h
toluene; 110 °C; 20 h
CH2Cl2; 40 °C; 24 h
CH2Cl2; 22 °C; 1 h
3
Me
9a
4
Me
isoprene
10a
11a
3b
93; 70:30 (15% trans-isomers)
5
Me
PhCH=CHCH(Me)=CH2
cyclopentadiene
1,3-cyclohexadiene
(CH2=CMe)2
51; 89:11b
6
(CH2)4Me (1b)
(CH2)4Me
(CH2)4Me
(CH2)4Me
(CH2)4Me
(CH2)2Ph (1c)
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
CH2OAc (1d)
CH2OAc
CH2OAc
H (1e)
90; >96:4
7
toluene; 110 °C; 20 h
CH2Cl2; 22 °C; 68 h
toluene; 110 °C; 20 h
CH2Cl2; 40 °C; 24 h
CH2Cl2; 22 °C; 3 h
4b
79; 92:8 (5% trans-isomers)
8
9b
74
9
isoprene
10b
11b
3c
93; 71:29 (20% trans-isomers)
10
11
12
13
14
15
16
17
18
19
20
PhCH=CHCH(Me)=CH2
cyclopentadiene
1,3-cyclohexadiene
(CH2=CMe)2
65; 92:8b
83; >96:4
toluene; 110 °C; 18 h
toluene; 110 °C; 16 h
toluene; 110 °C; 18 h
CH2Cl2; 22 °C; 3 h
4c
78; 92:8b (5% trans-isomers)
9c
85
isoprene
10c
3d
87; 55:45 (20% trans-isomers)
cyclopentadiene
(CH2=CMe)2
81; >96:4
67
toluene; 80 °C; 18 h
CH2Cl2; 40 °C; 24 h
CH2Cl2; 22 °C; 2.5 h
toluene; 110 °C; 20 h
toluene; 110 °C; 18 h
9d
PhCH=CHCH(Me)=CH2
cyclopentadiene
1,3-cyclohexadiene
(CH2=CMe)2
11d
3e
55; 95:5b
77; >96:4
42; >96:4
79
H
4e
H
9e
a Yields refer to cycloadducts purified by flash chromatography; diastereomeric ratio (dr) refers to the dr of crude reaction mixtures determined by 1H NMR
spectroscopy.
b Purification gave diastereomerically pure products.
acid moiety by DIPEA and addition of two equivalents of
SnCl4 led to an enhanced directing effect by the acyl group
and a faster reaction. The use of the DIPEA/SnCl4 protocol
greatly enhanced the rate of reaction, which alleviated the
isomerization issues that occurred in the thermal reactions
of 1a–c with 1,3-cyclohexadiene (Table 2, entries 1, 3, and
7). The use of the DIPEA/SnCl4 protocol greatly enhanced
reaction rate for the reaction of 1b and 1c with 2,3-dimeth-
yl-1,3-butadiene without isomerization (entries 5 and 9).
Unfortunately, there was no enhancement in the regioselec-
tivity and lower yields in the Sn-catalyzed reaction of 1a–c
with isoprene (data not shown). Sc(OTf)3 was an effective
catalyst, with faster reaction rates for the reaction of 1b
with 1,3-cyclohexadiene and no evidence for isomerization
(entry 4). We saw an enhancement of the regioselectivity
for the reaction of isoprene with 1a–c (entries 2, 6, and 10),
although longer reaction times led to lower yields due to
unidentified side reactions. The cycloadducts of 1c, which
have a phenyl group, decomposed to complex mixtures in
the presence of Sc(OTf)3 (entries 8 and 10), so its usefulness
was severely limited for the reactions of 1c. Low yields of
cycloadducts 11 were obtained for the reaction of 1a–d
with (E)-3-methyl-1-phenyl-1,3-butadiene catalyzed by
Sc(OTf)3 or the DIPEA/SnCl4 protocol, also presumably due
to the side reactions caused by the presence of the phenyl
ring.
In exploring the Lewis acid catalyzed Diels–Alder reac-
tion of 1, we uncovered the tendency for some of the cy-
cloadducts, especially the bicyclic compounds 3 and 4, to
undergo isomerization to give the acyl group in the exo-po-
sition. Several studies have noted the tendency for cis-di-
endo cycloadducts of cyclopentadiene to isomerize to the
more stable trans-compounds.15 When NaOH is added to
methanolic solutions of 3a–c and 4a–c, there is epimeriza-
tion at the α-carbon to the acyl group to give 12a–c (57–
88% yield) and 13a–c (51–86% yield), respectively (Scheme
3). The epimerization of nonbicyclic compounds (e.g., 9b)
occurs more slowly (1 h vs 24 h) and in lower yields under
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Table 2 Lewis Acid Catalyzed Diels–Alder Reaction of γ-Hydroxybutenolides 1 with Dienesa
OH
Lewis acid
R1
O
diene
4, 9, and 10
+
O
1
Entry
R1
Me (1a)
Diene
Catalyst
Product
Yield (%); drb
78; >96:4
1
2
1,3-cyclohexadiene
isoprene
DIPEA/SnCl4
Sc(OTf)3
4a
10a
4b
Me
23; 88:12 (~5% trans)
78; >96:4
3
(CH2)4Me (1b)
(CH2)4Me
(CH2)4Me
(CH2)4Me
(CH2)2Ph (1c)
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
1,3-cyclohexadiene
1,3-cyclohexadiene
(CH2=CMe2)2
DIPEA/SnCl4
Sc(OTf)3
4
4b
67; >96:4
5
DIPEA/SnCl4
Sc(OTf)3
9b
80
6
isoprene
10b
4c
57; 86:14 (~5% trans)
70; >96:4
7
1,3-cyclohexadiene
1,3-cyclohexadiene
(CH2=CMe2)2
DIPEA/SnCl4
Sc(OTf)3
8
4c
9; >96:4 (20% trans)
83
9
DIPEA/SnCl4
Sc(OTf)3
9c
10
isoprene
10c
21; 80:20 (~5% trans)
a All reactions were performed in CH2Cl2 for 1 h; DIPEA/SnCl4 reactions were performed at 0 °C and Sc(OTf)3 reactions at 22 °C.
b Yields refer to cycloadducts purified by flash chromatography; diastereomeric ratio (dr) refers to the dr of crude reaction mixtures determined by 1H NMR
spectroscopy.
similar reaction conditions. A simple one-pot procedure
was developed, in which the Diels–Alder reaction was run
in methanol and the base is added directly to the crude cy-
cloadduct, for the synthesis of 12a–c from 1a–c (78–81%
yield).16–20 Amine bases such as DIPEA and triethylamine
also gave isomerization but at slower rates. With the Diels–
Alder reaction of γ-hydroxybutenolides and β-acylacrylic
acids, and this isomerization reaction, three of the possible
four diastereomers of these bicyclic compounds are readily
prepared.
diovascular events, have a tricyclic core attainable using the
methodology described herein. We envisioned a regio- and
diastereoselective Diels–Alder reaction establishing the ste-
reogenic centers of the A/B ring and C-4, with the stereo-
genic center at C-3 established by the reduction or alkyla-
tion of the Diels–Alder products. Employing the Diels–Alder
reaction in the synthesis of himbacine and their derivatives
has been a common and highly successful strategy, with
most approaches using an intramolecular Diels–Alder reac-
tion to prepare the tricyclic core,23–26 although there are re-
ports using an intermolecular Diels–Alder reaction.27,28
n
OH–, MeOH
O
3a–c
4a–c
H
H
COR1
CO2H
O
N
O
O
O
H
H
12a–c; n = 1 (57–88% yield)
13a–c; n = 2 (51–86% yield)
H
C
B
A
O
3
OH–, MeOH
4
N
12a–c
1a–c
(56–78% yield)
MeOH
Scheme 3 Isomerization of 3 and 4
N
himbacine
In considering the application of the Diels–Alder reac-
tion of γ-hydroxybutenolides to the synthesis of biological-
ly important molecules, we immediately recognized com-
pounds such as himbacine and related pharmaceuticals
(e.g., vorapaxar) as potential targets (Figure 1).21–28 Himba-
cine, a powerful muscarinic receptor antagonist that was
proposed as a potential candidate for treating Alzheimer’s
disease, and vorapaxar,22 a thrombin receptor antagonist
recently approved by the FDA for reducing the risk of car-
F
vorapaxar
Figure 1 Structures of himbacine and vorapaxar
For our model studies, we prepared diene 14 in three
steps from cyclohexanone (see Supporting Information),
which incorporated a simple isobutyl group that was a
stand-in for the more complicated substituents normally
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W. H. Miles et al.
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Synthesis
found at C-4 in himbacine-related compounds. The Diels–
Alder reaction of 1a and 1e with diene 14 gave Diels–Alder
products 15a and 15b, respectively, in good yields (Scheme
4). In both cases, the dr of the crude products was >90:10,
which upon purification gave cycloadducts 15a and 15b
free of diastereomeric impurities. The selective formation
of 15a and 15b reflects an endo transition state as well as
the formyl or acyl group acting as a strong ‘ortho’-directing
group.
achieved using the in situ-generated titanium reagent (93%
yield). Recrystallization of 16a from hexanes gave crystals
suitable for X-ray diffraction studies, which conclusively es-
tablished the stereochemical assignment of 16a and 16b
(Figure 2).
CO2H
COR1
OH
40 °C
R1
O
+
O
1
a: R1 = Me
e: R1 = H
14
15a (R1 = Me); 80%; dr 9:1
15b (R1 = H); 84%; dr >9:1
MeTi(Oi-Pr)3
NaBH4
O
O
O
Figure 2 X-ray crystal structure of 16a
O
This study establishes γ-hydroxybutenolides as excel-
lent dienophiles in the Diels–Alder reaction. Reactive
dienes gave good yields of cycloadducts under thermal con-
ditions, although isomerization of the γ-hydroxybuteno-
lides was evident with less reactive dienes such as 1,3-cy-
clohexadiene and isoprene. In some cases, this issue was
overcome by employing Lewis acids, which also lead to en-
hanced stereo- and regioselectivity. The tendency for γ-hy-
droxybutenolides to isomerize to the more stable (E)-acyl-
acrylic acids is a problem that still needs to be addressed in
the case for less reactive dienes. These cycloadducts have
the potential for transformation to stereochemically de-
fined γ-lactones as evidenced by the stereoselective reduc-
tion of 15a and the alkylation of 15b. Even though the com-
pletion of the synthesis of the tricyclic core of himbacine
awaits the development of a stereoselective trans-reduc-
tion of the alkenyl moiety, the potential for the synthesis of
himbacine derivatives has been demonstrated. The devel-
opment of an enantioselective version to give scalemic cy-
cloadducts will be the next challenge. In conclusion, this
study demonstrates some of the potential of γ-hydroxy-
butenolides as dienophiles in the Diels–Alder reaction,
which promises to be an important contributor to the syn-
thesis of γ-lactones and related compounds.
16a
93%; dr >95:5
Scheme 4 Synthesis of 16a and 16b
16b
69%; dr >95:5
With access to both 15a and 15b, the stage was set for
the establishment of the C-3 stereogenic center of the lac-
tone ring. The reduction of cyclic γ-keto acids developed by
Rovis29 and others30 for the formation of the C-3 stereogenic
center was clearly relevant and served as a guide for our
studies. The γ-keto acids of these studies, most lacking a
substituent at the stereogenic center of ‘C-4’, gave anti-
products (corresponding to compound 16a) with Ph2MeSiH/
CF3CO2H, and syn-products (corresponding to compound
16b) with hydride reagents. Our studies with the additional
stereogenic center at ‘C-4’ gave the opposite stereochemical
results. Reduction of 15a with typical hydride reagents
[NaBH4, DIBAL, Zn(BH4)2] gave good yields and high diaste-
reoselectivity (>95:5) of 16b (Scheme 4). Employing Rovis’
protocol using silanes (Et3SiH, Ph2MeSiH) with CF3CO2H,
16a was obtained with modest stereoselectivity but in low
yields. Our results clearly show the importance of the ‘C-4’
stereogenic center in determining the stereochemical out-
come for the reduction of cyclic γ-keto acids.29 The alkyl-
ation of 15b was then explored as an alternative approach
to the desired lactone 16a. The addition of MeLi in Et2O
gave a 78% yield of the lactone products but with poor dia-
stereoselectivity (77:23 dr; 16a:16b). Excellent diastereose-
lectivity (>95:5) for the desired lactone was achieved using
MeMgBr, Me2CuLi, and MeTi(O-iPr)3, with the highest yields
All reactions were carried out under argon. All glassware was dried in
the oven (110 °C) before use. Yields refer to isolated compounds that
are greater than >95% pure as determined by 1H and 13C NMR spec-
troscopy. IR spectra were obtained on an FT-IR spectrophotometer.
The 1H and 13C NMR were recorded at 400 MHz and 100 MHz, respec-
tively. All chemical shifts in the 1H NMR are reported in ppm relative
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W. H. Miles et al.
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Synthesis
to TMS (δ = 0.00) or CHCl3 (δ = 7.26) and in the 13C NMR are reported
in ppm relative to CDCl3 (δ = 77.16). Flash chromatography was per-
formed on 60 Å silica gel (40–75 μm). CH2Cl2 and toluene were dried
over molecular sieves. Single crystals of 16a were prepared by recrys-
tallization from hexanes. X-ray data were acquired at 173 K on a
Bruker Smart Apex CCD diffractometer employing graphite mono-
chromated MoKα radiation (δ = 0.71073 Å). The Bruker Apex2 suite of
program31 was used to process the data and the Bruker SAINT soft-
ware package32 was used to integrate the frames with a narrow-frame
algorithm. The multi-scan method (SADABS)33 was used to correct
the data for absorption effects. The Bruker SHELXTL software pack-
age34 was used to perform structure solution by direct methods, and
refinement by full-matrix least-squares on F2. All non-hydrogen at-
oms were refined anisotropically with suggested weighting factors
and the hydrogens were calculated on a riding model. All cif files
were validated with the checkCIF/Platon facility of IUCr that was ac-
cessed with the software program enCIFer. High-resolution mass
spectra were obtained using a direct analysis in real time – time-of-
flight (DART-TOF) mass spectrometer.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C11H15O3: 195.1021; found:
195.1023.
(1S*,6R*)-6-Acetyl-3,4-dimethylcyclohex-3-enecarboxylic Acid
(9a)
White solid; yield: 0.570 g [94% based on 0.352 g (3.08 mmol) of 1a in
15 mL of CH2Cl2]; mp 110.5–113 °C.
IR (CH2Cl2): 3300–2700, 1746, 1709 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.04 (dt, J = 3.6, 6.2 Hz, 1 H), 2.84 (dt,
J = 3.6, 6.8 Hz, 1 H), 2.51–2.22 (m, 4 H), 2.19 (s, 3 H), 1.64 (s, 3 H), 1.62
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 208.3, 179.0, 123.7, 122.5, 46.9, 39.1,
31.1, 30.7, 26.8, 18.2, 18.0.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C11H17O3: 197.1178; found:
197.1179.
(1S*,6R*)-6-Acetyl-3-methylcyclohex-3-enecarboxylic Acid (10a)
Pale yellow oil; yield: 0.214 g [93% based on 0.144 g (1.26 mmol) of
1a]; 10a:iso-10a (15% trans-isomers) = 70:30.
Thermal Diels–Alder Reaction of 1 with Dienes; General Procedure
(Table 1)
IR (CH2Cl2): 3400–2800, 1746, 1709 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.95 (br s, 1 H), 5.39 (br s, 1 H), 3.04
(m, 1 H), 2.85 (m, 1 H), 2.54–2.20 (m, 4 H), 2.17 (s, 3 H), 1.65 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 209.3, 179.9, 133.3, 118.6, 47.0, 39.9,
30.6, 27.8, 25.8, 23.4.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C10H15O3: 183.1021; found:
183.1023.
A solution of 1 (1.0–1.3 mmol) and respective diene (3–5 equiv) in
CH2Cl2 (5 mL) or toluene (5 mL) was stirred for the time and tempera-
ture specified in Table 1. The reactions employing toluene at 110 °C
were done in a sealed tube. The volatiles were removed on the rotary
evaporator and the crude product was purified by flash chromatogra-
phy (silica gel; hexanes → 50% EtOAc in hexanes) to give 3, 4, 9, 10, or
11. For convenience, the Diels–Alder products are listed as the chain
tautomer even when the ring tautomers are the major species. NOE
experiments established the major ring tautomers of 3a and 4a as 7a
and 8a, respectively; the assignment of the ring tautomers of 3b–d,
4b, and 4c was based on chemical shift arguments of the alkenyl pro-
tons of these compounds compared to the alkenyl protons of 3a and
4a.
(1R*,2R*,3S*)-2-Acetyl-5-methyl-3-phenylcyclohex-4-ene-1-car-
boxylic Acid (11a)
White solid; yield: 0.139 g [51% based on 0.120 g (1.05 mmol) of 1a];
11a:iso-11a = 89:11 (crude); mp 140 °C (dec.).
IR (CH2Cl2): 3300–2700, 1744, 1711, 1603 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.32 (br t, J = 7.1 Hz, 2 H), 7.24 (m, 1 H),
7.17 (d, J = 7.0 Hz, 2 H), 5.42 (br s, 1 H), 3.85 (br s, 1 H), 3.60 (dd, J =
3.7, 6.6 Hz, 1 H), 3.01 (m, 1 H), 2.86 (m, 1 H), 2.33 (dd, J = 6.2, 17.2 Hz,
1 H), 1.84 (s, 3 H), 1.39 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 210.9, 180.3, 142.0, 135.6, 128.8,
128.4, 127.2, 120.7, 49.9, 44.5, 43.2, 33.7, 29.8, 23.6.
(1R*,2S*,3R*,4S*)-3-Acetylbicyclo[2.2.1]hept-5-ene-2-carboxylic
Acid (3a)16
White solid; yield: 0.205 g [99% based on 0.131 g (1.15 mmol) of 1a];
>96:4 dr; 3a:5a:7a = 40:15:45; mp 76–77.5 °C.
1H NMR (400 MHz, CDCl3; 8% DABCO): δ = 6.99 (br s, 1 H), 6.23 (dd, J =
2.9, 5.5 Hz, 1 H), 6.20 (dd, J = 2.9, 5.5 Hz, 1 H), 3.39 (dd, J = 4.0, 9.2 Hz,
1 H), 3.22 (br s, 1 H), 3.17 (dd, J = 3.6, 9.2 Hz, 1 H), 3.12 (br s, 1 H), 1.83
(s, 3 H), 1.54 (br d, J = 8.4 Hz, 1 H), 1.39 (br d, J = 8.4 Hz, 1 H).
HRMS (DART-TOF): m/z [M + 1]+ calcd for C16H19O3: 259.1334; found:
259.1337.
13C NMR (100 MHz, CDCl3; 8% DABCO): δ = 177.3, 135.7, 134.4, 54.0,
50.7, 49.2, 46.1, 45.6, 44.4, 28.4.
(1R*,2S*,3R*,4S*)-3-Hexanoylbicyclo[2.2.1]hept-5-ene-2-carboxyl-
ic Acid (3b)
White solid; yield: 0.263 g [90% based on 0.211 g (1.24 mmol) of 1b];
>96:4 dr; 3b:5b:7b = 61:18:21; mp 69–71 °C.17
(1R*,2S*,3R*,4S*)-3-Acetylbicyclo[2.2.2]oct-5-ene-2-carboxylic
Acid (4a)
IR (CH2Cl2): 3536, 1765, 1712 cm–1
.
Off-white solid; yield: 0.186 g [74% based on 0.147 g (1.29 mmol) of
1a]; >96:4 dr; 6a:8a = 30:70; mp 126–127.5 °C.
1H NMR (400 MHz, CDCl3; 8 mol% DABCO): δ = 7.44 (br s, 1 H), 6.26
(dd, J = 2.9, 5.5 Hz, 1 H), 6.18 (dd, J = 2.9, 5.5 Hz, 1 H), 3.32 (dd, J = 3.6,
9.2 Hz, 1 H), 3.26 (br d, J = 8.8 Hz, 1 H), 3.20 (br s, 1 H), 3.12 (br s, 1 H),
2.16 (br s, 2 H), 1.55–1.23 (m, 8 H), 0.89 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3; 30 mol% DABCO): δ = 177.0, 135.3, 134.6,
54.1, 49.8, 49.7, 46.4, 46.2, 42.8, 31.7, 23.5, 22.7, 14.1.
IR (CH2Cl2): 3567, 1771 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.38 (m, 0.3 H), 6.31 (m, 0.3 H), 6.25–
6.20 (m, 1.4 H) 3.75 (br s, 0.7 H), 3.24 (br s, 0.3 H), 3.18–3.08 (m, 1.7
H), 3.02 (dd, J = 3.7, 9.9 Hz, 0.3 H), 2.92 (m, 0.3 H), 2.79 (m, 0.7 H), 2.56
(dd, J = 2.6, 9.9 Hz, 0.3 H), 2.51 (dd, J = 2.4, 8.6 Hz, 0.7 H), 1.592 (s, 2.1
H), 1.585 (s, 0.9 H), 1.56–1.49 (m, 12 H), 1.33–1.24 (m, 2 H).
HRMS (DART-TOF): m/z [M + 1]+ calcd for C14H21O3: 237.1491; found:
237.1495.
13C NMR (100 MHz, CDCl3; 30% DABCO): δ = 177.9, 133.3, 132.5, 114.6
(br), 49.6, 47.5, 32.0, 30.7, 26.5, 25.0, 22.7.
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W. H. Miles et al.
Paper
Synthesis
(1R*,2S*,3R*,4S*)-3-Hexanoylbicyclo[2.2.2]oct-5-ene-2-carboxylic
(1R*,2S*,3R*,4S*)-3-(3-Phenylpropanoyl)[2.2.1]hept-5-ene-2-car-
Acid (4b)
boxylic Acid (3c)
White solid; yield: 0.245 g [79% based on 0.211 g (1.24 mmol) of 1b];
92:8 dr; 6b:8b (~5% trans-isomers) = 59:41; mp 105–107 °C.
White solid; yield: 0.257 g [83% based on 0.234 g (1.15 mmol) of 1c];
>96:4 dr; 3c:5c:7c = 62:18:20; mp 84–86 °C.
IR (CH2Cl2): 3570, 1768 cm–1
.
IR (CH2Cl2): 3565, 1768, 1714 cm–1
.
1H NMR (400 MHz, CDCl3; 12 mol% DABCO): δ = 6.32–6.24 (m, 2 H),
4.12 (br s, 1 H), 3.11 (br s, 1 H), 3.01 (dd, J = 3.7, 9.5 Hz, 1 H), 2.81 (br s,
1 H), 2.55 (br d, J = 9.5 Hz, 1 H), 1.84–1.74 (m, 2 H), 1.55–1.24 (m, 10
H), 0.90 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3; 12 mol% DABCO): δ = 177.4, 133.5, 132.9,
116.0, 48.7, 47.8, 40.4, 32.0, 31.9, 30.4, 24.9, 22.9, 22.8, 22.7, 14.1.
1H NMR (400 MHz, CDCl3; 20 mol% DABCO): δ = 7.92 (br s, 1 H), 7.27
(m, 2 H), 7.21–7.16 (m, 3 H), 6.23 (dd, J = 2.8, 5.3 Hz, 1 H), 6.13 (dd, J =
2.9, 5.5 Hz, 1 H), 3.34 (dd, J = 3.7, 9.5 Hz, 1 H), 3.24 (dd, J = 3.3, 9.5 Hz,
1 H), 3.18 (br s, 1 H), 3.07 (br s, 1 H), 2.93–2.76 (m, 2 H), 2.62–2.47 (m,
2 H), 1.47 (d, J = 8.4 Hz, 1 H), 1.33 (d, J = 8.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3; 20 mol% DABCO): δ = 177.3, 141.4, 135.3,
134.6, 128.6, 128.4, 126.1, 54.3, 49.8, 49.4, 46.4, 46.1, 44.2, 29.9.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C17H19O3: 271.1334; found:
HRMS (DART-TOF): m/z [M + 1]+ calcd for C15H23O3: 251.1647; found:
251.1651.
271.1343.
(1S*,6R*)-6-Hexanoyl-3,4-dimethylcyclohex-3-enecarboxylic Acid
(9b)
(1R*,2S*,3R*,4S*)-3-(3-Phenylpropanoyl)[2.2.2]oct-5-ene-2-car-
boxylic Acid (4c)
White solid; yield: 0.231 g [74% based on 0.211 g (1.24 mmol) of 1b];
mp 75–77 °C.
IR (CH2Cl2): 3300–2700, 1746, 1706 cm–1
1H NMR (400 MHz, CDCl3): δ = 2.99 (dt, J = 3.5, 6.6 Hz, 1 H), 2.87 (dt,
J = 3.7, 6.6 Hz, 1 H), 2.54–2.21 (m, 4 H), 2.46 (t, J = 7.3 Hz, 2 H), 1.64 (s,
3 H), 1.62 (s, 3 H), 1.56 (pent, J = 7.4 Hz, 2 H), 1.34–1.20 (m, 4 H), 0.88
(t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 211.5, 179.9, 124.9, 123.5, 47.4, 40.1,
40.0, 32.1, 31.8, 31.5, 23.4, 22.6, 19.2, 19.0, 14.1.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C15H25O3: 253.1804; found:
253.1809.
White solid; yield: 0.244 g [78% based on 0.224 g (1.10 mmol) of 1c];
92:8 dr; 6c:8c (~5% trans-isomers) = 59:41; mp 115.5–118 °C.
.
IR (CH2Cl2): 3564, 1769 cm–1
.
1H NMR (400 MHz, CDCl3; 30 mol% DABCO): δ = 7.32–7.17 (m, 5 H),
6.31–6.25 (m, 2 H). 4.14 (br s, 1 H), 3.11 (m, 1 H), 3.05 (dd, J = 3.7, 9.5
Hz, 1 H), 2.84–2.78 (m, 3 H), 2.59 (dd, J = 2.2, 9.5 Hz, 1 H), 2.23–2.10
(m, 2 H), 1.57–1.45 (m, 2 H), 1.36 (m, 2 H).
13C NMR (100 MHz, CDCl3; 30 mol% DABCO): δ = 177.4, 141.2, 133.6,
132.8, 128.7, 128.5, 126.3, 120.9, 49.5, 48.0, 42.2, 32.2, 30.5, 29.6,
24.9, 23.0.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C18H21O3: 285.1491; found:
285.1497.
(1S*,6R*)-6-Hexanoyl-3-methylcyclohex-3-enecarboxylic Acid
(10b)
(1S*,6R*)-3,4-Dimethyl-6-(3-phenylpropanoyl)cyclohex-3-enecar-
boxylic Acid (9c)
Oil; yield: 0.273 g [93% based on 0.211 g (1.24 mmol) of 1b]; 10b:iso-
10b (20% trans-isomers) = 71:29.
White solid; yield: 0.286 g [85% based on 0.241 g (1.18 mmol) of 1c];
mp 102–104 °C.
IR (CH2Cl2): 1746, 1707 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.37 (m, 1 H), 3.00 (m, 1 H), 2.91 (m, 1
H), 2.60–2.20 (m, 5 H), 1.67 (s, 3 H), 1.61–1.52 (m, 3 H), 1.35–1.20 (m,
5 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 211.4, 179.9, 133.4, 119.08, 46.4, 39.9,
31.4, 30.5, 25.8, 23.41, 23.38, 22.6, 14.0.
IR (CH2Cl2): 3300–2700, 1746, 1708 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.27 (m, 2 H), 7.21–7.16 (m, 3 H), 3.01
(m, 1 H), 2.93–2.78 (m, 5 H), 2.50 (dd, J = 5.2, 17.5 Hz, 1 H), 2.42–2.12
(m, 3 H), 1.61 (br s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 210.2, 179.8, 141.4, 128.6, 128.5,
126.2, 124.9, 123.4, 47.6, 41.8, 40.1, 32.1, 31.7, 29.7, 19.2, 19.0.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C14H23O3: 239.1647; found:
239.1696.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C18H23O3: 287.1647; found:
287.1658.
(1R*,2R*,3S*)-2-Hexanoyl-5-methyl-3-phenylcyclohex-4-ene-1-
carboxylic Acid (11b)
(1S*,6R*)-3-Methyl-6-(3-phenylpropanoyl)cyclohex-3-enecarbox-
ylic Acid (10c)
White solid; yield: 0.183 g [65% based on 0.153 g (0.90 mmol) of 1b];
>96:4 dr; mp 160 °C (dec).
White solid; yield: 0.260 g [87% based on 0.225 g (1.10 mmol) of 1c];
10c:iso-10c (20% trans-isomers) = 55:45; mp 64–72 °C.
IR (CH2Cl2): 3300–2700, 1745, 1711 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29 (br t, J = 7.1 Hz, 2 H), 7.23 (m, 1 H),
7.14 (m, 2 H), 5.41 (br s, 1 H), 3.82 (br s, 1 H), 3.52 (dd, J = 3.6, 7.0 Hz,
1 H), 3.01 (m, 1 H), 2.87 (m, 1 H), 2.33 (dd, J = 5.9, 17.2 Hz, 1 H), 2.06
(m, 1 H), 1.83 (s, 3 H), 1.25–0.78 (m, 7 H), 0.74 (t, J = 7.0 Hz, 3 H).
IR (CH2Cl2): 1745, 1708 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.16 (m, 5 H), 5.33 (br s, 1 H),
3.08–2.78 (m, 6 H), 2.50–2.20 (m, 4 H), 1.66 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 212.4, 180.3, 142.1, 135.6, 128.7,
128.4, 127.1, 120.8, 49.6, 46.3, 44.7, 43.2, 31.0, 30.0, 23.6, 22.4, 22.2,
14.0.
13C NMR (100 MHz, CDCl3): δ = 210.2, 179.8, 141.3, 133.4, 128.5,
128.4, 126.1, 118.5, 46.5, 41.7, 39.9, 30.5, 29.7, 25.6, 23.5.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C17H21O3: 273.1491; found:
273.1491.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C20H27O3: 315.1960; found:
315.1975.
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931
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Synthesis
(1R*,2S*,3R*,4S*)-3-(2-Acetoxyacetyl)bicyclo[2.2.1]hept-5-ene-2-
IR (CH2Cl2): 3578, 1773 cm–1
.
carboxylic Acid (3d)
1H NMR (400 MHz, CDCl3): δ = 6.29 (m, 1 H), 6.24 (m, 1 H), 5.34 (dd,
J = 1.8, 4.0 Hz, 1 H), 3.61 (d, J = 4.4 Hz, 1 H), 3.08 (m, 1 H), 2.95 (dd, J =
3.7, 9.5 Hz, 1 H), 2.86 (m, 1 H), 2.50 (dt, J = 9.5, 2.4 Hz, 1 H), 1.58–1.50
(m, 2 H), 1.36–1.25 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 179.0, 134.1, 132.7, 102.7, 47.2, 45.9,
31.9, 31.8, 23.6, 23.3.
Off-white solid; yield: 0.233 g [81% based on 0.206 (1.21 mmol) of
1d]; 3d:5d:7d = 4:53:43; mp 66–70 °C.
IR (CH2Cl2): 3552, 1775, 1751 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.37 (dd, J = 2.9, 5.5 Hz, 0.55 H), 6.28
(dd, J = 3.3, 5.9 Hz, 0.45 H), 6.22 (dd, J = 2.9, 5.5 Hz, 0.55 H), 6.15 (dd,
J = 2.8, 5.6 Hz, 0.45 H), 4.28 (d, J = 12.1 Hz, 0.45 H), 4.25 (d, J = 12.1 Hz,
0.55 H), 4.13 (d, J = 11.7 Hz, 0.45 H), 4.04 (d, J = 11.7 Hz, 0.55 H), 3.88
(br s, 0.45 H), 3.63 (br s, 0.55 H), 3.55 (dd, J = 5.0, 8.6 Hz, 0.45 H), 3.43
(dd, J = 5.0, 8.9 Hz, 0.55 H), 3.32 (m, 1 H), 3.18 (m, 1 H), 3.03 (m, 1 H),
2.16 (s, 1.35 H), 2.12 (s, 1.65 H), 1.71–1.61 (m, 1 H), 1.49-1.43 (m, 1
H).
13C NMR (100 MHz, CDCl3): δ = 177.0, 175.6, 170.82, 170.76, 136.9,
136.7, 134.1, 133.7, 104.4, 103.8, 69.0, 65.8, 53.2, 52.0, 50.6, 49.9,
47.9, 47.6, 45.8, 45.0, 44.8, 43.9, 20.83, 20.76.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C12H15O5: 239.0919; found:
239.0921.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C10H13O3: 181.0865; found:
181.0861.
(1S,6R)-6-Formyl-3,4-dimethylcyclohex-3-enecarboxylic Acid
(9e)35
Colorless oil; yield: 0.146 g [79% based on 0.102 g (1.02 mmol) of 1e];
>96% ring tautomer.
IR (CH2Cl2): 3577, 1778 cm–1
.
1H NMR (400 MHz, CDCl3; 4 mol% DABCO): δ = 6.34 (br s, 1 H), 4.15
(br s, 1 H), 3.06 (dt, J = 7.5, 3.9 Hz, 1 H), 2.63 (q, J = 7.2 Hz, 1 H), 2.39
(m, 1 H), 2.29–2.15 (m, 2 H), 1.96 (dd, J = 16.9, 6.6 Hz, 1 H), 1.65 (s, 6
H).
13C NMR (100 MHz, CDCl3; 4 mol% DABCO): δ = 178.9, 125.0, 123.9,
44.6, 41.1, 37.7, 30.1, 29.2, 19.4, 19.1 (hemi-acetal carbon was not ob-
served).
(1S*,6R*)-6-(2-Acetoxyacetyl)-3,4-dimethylcyclohex-3-enecarbox-
ylic Acid (9d)
Tan solid; yield: 0.211 g [67% based on 0.206 g (1.24 mmol) of 1d];
9d:9d-ring tautomers = 93:7; mp 102–103.5 °C.
IR (CH2Cl2): 1783, 1750, 1707 cm–1
1H NMR (400 MHz, CDCl3): δ = 11.05 (br s, 1 H), 4.82 (s, 2 H), 3.06 (m,
1 H), 2.98 (m, 1 H), 2.51 (dd, J = 5.0, 17.4 Hz, 1 H), 2.36–2.27 (m, 3 H),
2.15 (s, 3 H), 1.64 (br s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 203.7, 179.5, 170.5, 125.0, 122.9, 66.9,
44.3, 40.1, 31.8, 30.7, 20.5, 19.0, 18.9.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C13H19O5: 255.1232; found:
255.1239.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C10H15O3: 183.1021; found:
183.1023.
.
SnCl4-Promoted Diels–Alder Reaction of 1 with Dienes; General
Procedure (Table 2)
A solution of 1a, 1b, or 1c (1.20 mmol) with the respective diene [3–5
equiv; 1.3 equiv in the case of (E)-3-methyl-1-phenyl-1,3-butadiene]
in CH2Cl2 (5 mL) was cooled to 0 °C. DIPEA (0.22 mL, 1.26 mmol) and
SnCl4 (0.29 mL, 2.5 mmol) were added dropwise and the reaction
mixture was stirred for the 1 h at 0 °C. The mixture was quenched
with H2O (10 mL), the layers were separated, and the aqueous layer
was extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts
were washed with H2O (50 mL) and brine (50 mL), and dried over
Na2SO4. The volatiles were removed on the rotary evaporator and the
crude product was purified by flash chromatography (silica gel; hex-
anes → 50% EtOAc in hexanes). The yields and dr are summarized in
Table 2.
(1R*,2R*,3S*)-2-(2-Acetoxyacetyl)-5-methyl-3-phenylcyclohex-4-
ene-1-carboxylic Acid (11d)
White solid; yield: 0.174 g [55% based on 0.172 g (1.01 mmol) of 1d];
95:5 dr; mp 144–148 °C.
IR (CH2Cl2): 1745, 1727, 1702 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.33 (t, J = 7.3 Hz, 2 H), 7.26 (m, 1 H),
7.14 (d, J = 7.7 Hz, 2 H), 5.43 (br s, 1 H), 4.46 (d, J = 17.2 Hz, 1 H), 3.85
(br s, 1 H), 3.50 (m, 1 H), 3.16 (d, J = 16.8 Hz, 1 H), 3.10 (m, 1 H), 2.81
(m, 1 H), 2.39 (dd, J = 6.2, 17.6 Hz, 1 H), 1.99 (s, 3 H), 1.84 (br s, 3 H).
.
Sc(OTf)3-Catalyzed Diels–Alder Reaction of 1 with Dienes; General
Procedure (Table 2)
13C NMR (100 MHz, CDCl3): δ = 204.5, 179.0, 169.9, 141.3, 136.0,
129.0, 128.8, 128.2, 127.5, 127.1, 120.5, 69.9, 46.3, 44.5, 43.1, 30.0,
23.5, 20.5.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C18H21O5: 317.1389; found:
317.1394.
To a solution of 1 (1.2 mmol) and the respective diene (3–5 equiv) in
CH2Cl2 (5 mL) was added Sc(OTf)3 (0.12 g, 0.24 mmol) and the reac-
tion mixture was stirred for the time and temperature specified in Ta-
ble 2. The mixture was washed with H2O (2 × 20 mL), the volatiles
were removed on the rotary evaporator, and the crude product was
purified by flash chromatography (silica gel; hexanes → 50% EtOAc in
hexanes). The yields and dr are summarized in Table 2.
(1R*,2S*,3R*,4S*)-3-Formylbicyclo[2.2.1]hept-5-ene-2-carboxylic
Acid (3e)8
Isomerization of Diels–Alder Products 3a–c and 4a–c; General
Procedure
White solid; yield: 0.154 g [77% based on 0.120 g (1.00 mmol) of 1e];
>96:4 dr; 7e:5e = >98:2; mp 99–100 C (hexanes).
To a solution of 3a–c or 4a–c (0.5–1.1 mmol) in MeOH (1 mL) was
added NaOH (4–6 equiv) in MeOH (1.0 M). The reaction mixture was
stirred for 2 h and then quenched with 1.0 M aq HCl (4–6 mL). Brine
(10 mL) and EtOAc (10 mL) were added and the organic phase was
separated. The aqueous phase was extracted with EtOAc (2 × 10 mL),
the combined organic phases were washed with brine (10 mL), and
1H and 13C NMR spectra match with those described in the literature.8
(1R*,2S*,3R*,4S*)-3-Formylbicyclo[2.2.2]oct-5-ene-2-carboxylic
Acid (4e)
White solid; yield: 0.076 g [42% based on 1.00 g (1.00 mmol) of 1e];
>96:4 dr; 8e:6e = 95:5; mp 147–149 °C.
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W. H. Miles et al.
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Synthesis
dried over Na2SO4. The crude product was purified by flash chroma-
tography (silica gel; hexanes → 50% EtOAc in hexanes) to give 12a–c
and 13a–c.
13C NMR (100 MHz, CDCl3): δ = 210.4, 180.7, 134.6, 133.2, 53.7, 43.4,
41.4, 32.4, 32.2, 31.5, 24.3, 23.7, 22.6, 20.1, 14.1.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C15H23O3: 251.1647; found:
251.1655.
(1R*,2S*,3S*,4S*)-3-Acetylbicyclo[2.2.1]hept-5-ene-2-carboxylic
Acid (12a)2a
(1R*,2S*,3S*,4S*)-3-(3-Phenylpropanoyl)[2.2.2]oct-5-ene-2-car-
White solid; yield: 0.085 g [57% based on 0.149 g (0.083 mmol) of
boxylic Acid (13c)
3a]; mp 103–105 °C.
1H and 13C NMR spectra match with those described in the litera-
ture.2a
White solid; yield: 0.147 g [51% based on 0286 g (1.00 mmol) of 4c];
mp 113.5–115 °C.
IR (CH2Cl2): 3400–2800, 1742, 1705 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.28 (m, 2 H), 7.21–7.17 (m, 3 H), 6.36
(br t, J = 7.1 Hz, 1 H), 6.25 (br t, J = 7.0 Hz, 1 H), 3.30 (dd, J = 2.0, 5.6 Hz,
1 H), 3.05 (m, 1 H), 2.96–2.74 (m, 6 H), 1.59 (m, 1 H), 1.29–1.21 (m, 2
H), 1.01 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 209.1, 180.5, 141.1, 134.6, 133.2,
128.6, 128.5, 126.3, 53.4, 43.4, 43.1, 32.3, 32.2, 30.0, 24.3, 20.0.
(1R*,2S*,3S*,4S*)-3-Hexanoylbicyclo[2.2.1]hept-5-ene-2-carboxyl-
ic Acid (12b)
White solid; yield: 0.221 g [88% based on 0.250 (1.06 mmol) of 3b];
mp 92–94 °C.
IR (CH2Cl2): 3300–2750, 1744, 1703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.31 (dd, J = 2.9, 5.5 Hz, 1 H), 6.17 (dd,
J = 2.7, 5.7 Hz, 1 H), 3.46 (t, J = 4.2 Hz, 1 H), 3.27 (br s, 1 H), 3.01 (br s, 1
H), 2.77 (m, 1 H), 2.64–2.48 (m, 2 H), 1.64–1.25 (m, 8 H), 0.89 (t, J = 7.0
Hz, 3 H).
HRMS (DART-TOF): m/z [M + 1]+ calcd for C18H21O3: 285.1491; found:
285.1494.
One-Pot Procedure for the Synthesis of 12a–c from 1a–c; General
Procedure
13C NMR (100 MHz, CDCl3): δ = 210.8, 179.9, 137.8, 135.9, 54.6, 47.0,
46.7, 46.6, 45.4, 42.6, 31.5, 23.7, 22.6, 14.0.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C14H21O3: 237.1491; found:
237.1497.
To a solution of 1a, 1b, or 1c (1.0 mmol) in MeOH (5 mL) was added
1,3-cyclopentadiene (0.50 mL, 6.0 mmol) and the reaction mixture
was stirred for 4 h at 22 °C. Aq 2 M NaOH (5.0 mL, 10 mmol) was add-
ed and the mixture was stirred 0.5 h at 22 °C. The mixture was
quenched with aq 1 M HCl (15 mL). The aqueous phase was extracted
with EtOAc (2 × 25 mL), the combined organic phases were gently
washed with brine (50 mL), and dried over Na2SO4. The solvent was
removed on the rotary evaporator, and the crude product was puri-
fied by flash chromatography (silica gel; hexanes → 50% EtOAc in hex-
anes) to give 12a (78%), 12b (56%) or 12c (78%).
(1R*,2S*,3S*,4S*)-3-(3-Phenylpropanoyl)[2.2.1]hept-5-ene-2-car-
boxylic Acid (12c)
Off-white solid; yield: 0.202 g [74% based on 0.271 g (1.00 mmol) of
3c]; mp 60.5–62 °C.
IR (CH2Cl2): 3300–2700, 1744, 1706 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.28 (m, 2 H), 7.19 (m, 3 H), 6.26 (dd,
J = 3.3, 5.5 Hz, 1 H), 6.15 (dd, J = 2.9, 5.5 Hz, 1 H), 3.42 (t, J = 4.0 Hz, 1
H), 3.25 (br s, 1 H), 2.97–2.82 (m, 5 H), 2.75 (dd, J = 1.1, 4.4 Hz, 1 H),
1.47 (br d, J = 8.8 Hz, 1 H), 1.36 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 209.6, 179.4, 141.1, 137.8, 135.9,
128.6, 128.5, 126.3, 54.8, 46.8 (2 C), 46.5, 45.4, 44.2, 30.1.
(2S*,3R*,4S*)-3-Acetyl-4-isobutyl-1,2,3,4,5,6,7,8-octahydronaph-
thalene-2-carboxylic Acid (15a)
A solution of (E)-1-(3-methylbutylidene)-2-methylidenecyclohexane
(14; 1.026 g, 6.25 mmol; see Supporting Information) and 1a (0.530 g,
4.65 mmol) in CH2Cl2 (15 mL) was stirred at 40 °C for 20 h. After re-
moving the volatiles on the rotary evaporator, the crude product
(90:10 dr) was purified by flash chromatography (silica gel; 10 → 50%
EtOAc in hexanes) to give 15a as the chain tautomer; white solid;
yield: 1.04 g (80%); mp 104–107 °C.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C17H19O3: 271.1334; found:
271.1343.
(1R*,2S*,3S*,4S*)-3-Acetylbicyclo[2.2.2]oct-5-ene-2-carboxylic
IR (CH2Cl2): 3300–2500, 1752, 1708 1681 cm–1
.
Acid (13a)2a
White solid; yield: 0.089 g [86% based on 0.104 g (0.53 mmol) of 4a];
mp 104–106 °C.
1H NMR (400 MHz, CDCl3): δ = 3.38 (br s, 1 H) 2.90 (m, 1 H), 2.50–2.37
(m, 2 H) 2.24 (s, 3 H), 1.18–2.15 (m, 12 H), 0.88 (d, J = 6.2, 6 H).
1H and 13C NMR spectra match with those described in the litera-
ture.2a
13C NMR (100 MHz, CDCl3): δ = 211.8, 178.8, 128.8, 127.5, 51.2, 41.6,
40.2, 38.2, 32.0, 30.7 (2 C), 28.2, 26.1, 23.8, 23.5, 22.7, 21.7.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C17H27O3: 279.1960; found:
279.1964.
(1R*,2S*,3S*,4S*)-3-Hexanoylbicyclo[2.2.2]oct-5-ene-2-carboxylic
Acid (13b)
Pale yellow oil; yield: 0.0137 g [81% based on 0.169 g (0.67 mmol) of
(2S*,3R*,4S*)-3-Formyl-4-isobutyl-1,2,3,4,5,6,7,8-octahydronaph-
4b].
thalene-2-carboxylic Acid (15b)
IR (CH2Cl2): 3400–2700, 1741, 1707 cm–1
.
A solution of 14 (2.50 g, 15.2 mmol) and 1e (1.00 g, 10.0 mmol) in
CH2Cl2 (30 mL) was heated to 40 °C for 18 h. After removing the vola-
tiles on the rotary evaporator, the crude product was purified by flash
chromatography (silica gel; hexanes → 50% EtOAc in hexanes) to give
15b as the ring tautomer; white solid; yield: 2.22 g (84%); mp 108–
111 °C.
1H NMR (400 MHz, CDCl3): δ = 6.39 (t, J = 7.1 Hz, 1 H), 6.25 (br t, J = 7.1
Hz, 1 H), 3.30 (dd, J = 2.1, 5.5 Hz, 1 H), 3.06 (m, 1 H), 2.93–2.87 (m, 2
H), 2.58–2.42 (m, 2 H), 1.64–1.56 (m, 3 H), 1.37–1.22 (m, 6 H), 1.07
(m, 1 H), 0.87 (t, J = 7.0 Hz, 3 H).
IR (CH2Cl2): 3570, 1775 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 924–934

933
W. H. Miles et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 5.40 (br s, 1 H), 3.80 (br s, 1 H), 3.11
(m, 1 H), 2.66 (m, 1 H), 2.34–2.13 (m, 3 H), 1.97 (br s, 4 H), 1.70 (m, 1
H), 1.61–1.50 (m, 4 H), 1.42–1.23 (m, 2 H), 0.93 (d, J = 6.6 Hz, 3 H),
0.89 (d, J = 6.6 Hz, 3 H).
thank Lafayette College’s Academic Research Committee for financial
support. We gratefully acknowledge a grant from the Kresge Founda-
tion for the purchase of a 400 MHz NMR spectrometer.
13C NMR (100 MHz, CDCl3): δ = 180.8, 133.0, 130.8, 100.9, 46.3, 39.4,
37.0, 36.0, 30.7, 29.3, 27.7, 25.5, 23.4 (2C), 22.8, 22.5.
Supporting Information
HRMS (DART-TOF): m/z [M + 1]+ calcd for C16H25O3: 265.1804; found:
265.1807.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561348.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
(3S*,3aR*,4S*,9aS*)-4-Isobutyl-3-methyl-3a,4,5,6,7,8,9,9a-octahy-
dronaphtho[2,3-c]furan-1(3H)-one (16a)
References
To a solution of ClTi(O-iPr)3 (0.81 mL 3.50 mmol) in anhyd THF (6 mL)
at 0 °C was added MeLi (2.0 mL, 1.6 M in hexanes, 3.2 mmol) and the
reaction mixture was stirred for 1 h. After the mixture was warmed
to 22 °C, 15b (0.260 g, 0.985 mmol) was added and the mixture was
stirred at 22 °C for 19 h. The mixture was quenched with aq 1 M HCl
(40 mL), stirred vigorously for 15 min, and extracted with EtOAc (3 ×
50 mL). The combined organic extracts were washed with brine (50
mL) and dried over Na2SO4. The volatiles were removed on the rotary
evaporator and the crude product was purified by flash chromatogra-
phy (5% EtOAc in hexanes → 50% EtOAc in hexanes) to give 16a; white
solid; yield: 0.241 g (93%); mp 81–84 °C.
(1) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
G. Angew. Chem. Int. Ed. 2002, 41, 1668.
(2) (a) Miles, W. H.; Cohen, E. M.; Naimoli, B. J. Synth. Commun.
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(5) Simple γ-alkyl-γ-hydroxybutenolides are at slow exchange in
the 1H NMR at ambient temperature, with the presence of the
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IR (CH2Cl2): 1763 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.18 (dq, J = 4.2, 6.4 Hz, 1 H) 3.00 (qd,
J = 2.9, 8.2, 10.5 Hz, 1 H), 2.44 (dt, J = 4.5, 10.5 Hz, 1 H), 2.33 (dd, J =
2.8, 15.6 Hz, 1 H), 2.24–2.13 (m, 2 H), 1.99 (br s, 3 H) 1.67–1.49 (m, 6
H), 1.36 (m, 1 H), 1.35 (d, J = 6.2 Hz, 3 H), 1.19 (m, 1 H), 0.93 (d, J = 6.6
Hz, 3 H), 0.89 (d, J = 6.6 Hz, 3 H).
(6) For a review of the synthetic applications of γ-hydroxybuteno-
lides, see: Miles, W. H. Curr. Org. Synth. 2014, 11, 244.
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(9) (a) Noutsias, D.; Vassilikogiannakis, G. Org. Lett. 2012, 14, 3565.
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13C NMR (100 MHz, CDCl3): δ = 180.6, 133.0, 130.7, 77.3, 45.3, 39.4,
37.3, 37.0, 30.6, 29.3, 28.3, 25.6, 23.4, 23.2, 22.9, 22.7.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C17H27O2: 263.2011; found:
263.2017.
(3R*,3aR*,4S*,9aS*)-4-Isobutyl-3-methyl-3a,4,5,6,7,8,9,9a-octahy-
dronaphtho[2,3-c]furan-1(3H)-one (16b)
To a solution 15a (0.094 g, 0.38 mmol) in EtOH (2 mL) was added
NaBH4 (0.075 g, 0.19 mmol) and the reaction mixture was stirred for
1 h at 22 °C. H2O (10 mL) and aq 1 M HCl (10 mL) were added and the
mixture was stirred vigorously for 1 h. The mixture was extracted
with Et2O (3 × 30 mL), the combined organic extracts were washed
with brine (30 mL), dried over NaSO4, and concentrated on the rotary
evaporator. The crude product (16a:16b = 6:94) was purified by flash
chromatography (silica gel; 10 → 25% EtOAc in hexanes) to give 16b;
white solid; yield: 0.061 g (69%); mp 125–127 °C.
(10) (a) Lee, G. C. M.; Syage, E. T.; Harcourt, D. A.; Holmes, J. M.;
Garst, M. E. J. Org. Chem. 1991, 56, 7007. (b) Adam, W.;
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Recl. Trav. Chim. Pays-Bas 1987, 106, 469. (d) Cottier, L.;
Descotes, G.; Eymard, L.; Rapp, K. Synthesis 1995, 303.
(e) Annangudi, S. P.; Sun, M. J.; Salomon, R. G. Synlett 2005,
1468.
IR (CH2Cl2): 1765 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.67 (dq J = 5.0, 6.8 Hz, 1 H) 2.88 (ddd,
J = 5.0, 8.4, 11.2 Hz, 1 H), 2.48 (m, 1 H), 2.38 (m, 1 H), 2.25–1.88 (m, 6
H) 1.70–1.40 (m, 5 H), 1.50 (d, J = 6.6 Hz, 3 H), 1.25–1.12 (m, 2 H), 0.91
(d, J = 6.6 Hz, 3 H), 0.77 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 181.2, 134.6, 127.7, 79.0, 44.0, 39.6,
38.7, 37.0, 32,1, 30.6, 27.3, 26.3, 24.8, 23.4, 23.2, 21.3, 14.9.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C17H27O2: 263.2011; found:
263.2019.
(11) (a) Larson, R. T.; Pemberton, R. P.; Franke, J. M.; Tantillo, D. J.;
Thomson, R. J. J. Am. Chem. Soc. 2015, 137, 11197.
(b) Chackalamannil, S.; Wang, Y. G.; Greenlee, W. J.; Hu, Z. Y.;
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Fantuzzi, J.; Kurowski, S.; Graziano, M.; Chintala, M. J. Med.
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Acknowledgment
(12) Liu, P.; Pan, Y. M.; Hu, K.; Huang, X. C.; Liang, Y.; Wang, H. S. Tet-
rahedron 2013, 69, 7925.
Acknowledgment is made to the Donors of the American Chemical
Society Petroleum Research Fund for support of this research. We also
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934
W. H. Miles et al.
Paper
Synthesis
(13) Miles, W. H.; Duca, D. G.; Selfridge, B. R.; De Sousa, C. A. P.;
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(19) Canonne, P.; Plamondon, J.; Akssira, M. Tetrahedron 1988, 44,
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(14) In some cases, broadening of the peaks in the NMR spectra of
these cycloadducts may be attributable to hydrogen bonding;
see: Klika, K. D.; Tahtinen, P.; Dahlqvist, M.; Szabo, J. A.; Stajer,
G.; Sinkkonen, J.; Pihlaja, K. J. Chem. Soc., Perkin Trans. 2 2000,
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systems, see: (a) Suzuki, J.; Harada, T. Synthesis 2006, 2483.
(b) Miklos, F.; Sohar, P.; Csampai, A.; Sillanpaa, R.; Peter, M.;
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studies, the lack of certainty about the assignment of the ste-
reochemistry of compound ‘4’ in Pinnick’s paper is clarified.17 In
Pinnick’s study, the addition of lithium dimethylcuprate to
endo-Diels–Alder product of cyclopentadiene and maleic anhy-
dride gave a product whose NMR spectra match the spectra of
12a, and not 3a. A similar study by Walton, in which cadmium
reagents were added to above endo-Diels–Alder product,
appears to lead to isomerization since the melting points of
both 3a and 3b differ considerably from the values given in the
paper but are very close to the melting points found for isomer-
ized compounds 12a and 12b.18 A study of the addition of some
Grignard reagents to anhydrides has previously been noted to
cause isomerization of the resulting keto acids.19 The nickel-cat-
alyzed reactions of zinc reagents to anhydrides, on the other
hand, appears to occur without isomerization, since the
product from the above endo-Diels–Alder product exhibited a
complex 1H NMR spectra due to ‘rotomers,’ that is, ring and
chain tautomers.20
(23) Gao, L. J.; Waelbroeck, M.; Hofman, S.; Van Haver, D.; Milanesio,
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(27) Takadoi, M.; Katoh, T.; Ishiwata, A.; Terashima, S. Tetrahedron
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(32) Sheldrick, G. M. SADABS; University of Gottingen: Germany,
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(17) Cornelius, L. A. M.; Bone, R. G. A.; Hastings, R. H.; Deardorff, M.
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H. W. J. Org. Chem. 1993, 58, 3188.
(35) Cycloadduct 9e has been previously reported, but likely to be
the trans-compound: Andreev, V. M.; Usova, A. V. Bull. Acad. Sci.
USSR, Div. Chem. Sci. 1966, 15, 1351.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 924–934