Three-step metal-promoted allene-based preparation of Bis(heterocyclic) cyclophanes from carbonyl compounds

Article abstract of DOI:10.1021/jo500993x

A straightforward metal-mediated method for the synthesis of bis(dihydrofuryl) cyclophane scaffolds from carbonyl compounds has been developed. The combination of the dihydrofuran moiety with different heterocycles such as β-lactams and sugars allows high levels of skeletal diversity. The process comprises indium-promoted one-pot carbonyl bis(allenylation) and gold- or palladium-catalyzed double cyclization in the resulting bis(allenols), followed by selective ruthenium-catalyzed macrocyclization. In some cases, the method has been successfully applied to the synthesis of the challenging Z-isomers. The E- versus Z-stereochemistry of the metathesis-formed double bonds could not be assigned taking into consideration the usual coupling constants criteria, but a diagnostic based on the chemical shifts of the two olefinic protons located at the macrocyclic double bond was established.

Full text of DOI:10.1021/jo500993x

Article
pubs.acs.org/joc
Three-Step Metal-Promoted Allene-Based Preparation of
Bis(heterocyclic) Cyclophanes from Carbonyl Compounds
Benito Alcaide,*,† Pedro Almendros,*,‡ M. Teresa Quiros,† Carlos Lazaro,† and M. Rosario Torres§
́
́
†Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Organ
Química, Universidad Complutense de Madrid, 28040-Madrid, Spain
́
ica I, Unidad Asociada al CSIC, Facultad de
‡Instituto de Química Organ
§CAI Difraccion
́
ica General, IQOG-CSIC, Juan de la Cierva 3, 28006-Madrid, Spain
́
de Rayos X, Facultad de Química, Universidad Complutense de Madrid, 28040 Madrid, Spain
S
* Supporting Information
ABSTRACT: A straightforward metal-mediated method for
the synthesis of bis(dihydrofuryl) cyclophane scaffolds from
carbonyl compounds has been developed. The combination of
the dihydrofuran moiety with different heterocycles such as β-
lactams and sugars allows high levels of skeletal diversity. The
process comprises indium-promoted one-pot carbonyl bis-
(allenylation) and gold- or palladium-catalyzed double
cyclization in the resulting bis(allenols), followed by selective
ruthenium-catalyzed macrocyclization. In some cases, the
method has been successfully applied to the synthesis of the
challenging Z-isomers. The E- versus Z-stereochemistry of the
metathesis-formed double bonds could not be assigned taking into consideration the usual coupling constants criteria, but a
diagnostic based on the chemical shifts of the two olefinic protons located at the macrocyclic double bond was established.
due to its environmentally benign properties allied with a high
degree of chemo-, regio-, and diastereoselectivity,8 we decided
to pursue direct indium-mediated carbonyl bis(allenylation) for
the preparation of bis(allenols) and their double gold-catalyzed
cyclization to functionalized bis(dihydrofurans). Macrocyclic
entities are essential components of various types of bioactive
synthetic and natural products.9 Ring-closing metathesis
(RCM) has become a powerful tool for the construction of a
variety of cyclic structures, including macrocycles.10,11 In
connection with our current research interest in the area of
allenes and metals, we wish to describe herein a simple and
versatile approach to produce heterocyclic macrocycles
possessing two additional dihydrofurans in their structure.
Our approach relies on a sequential bis(allenylation)/bis-
(oxycyclization) followed by an RCM reaction that allows the
construction of macrocycles. The combination of the
dihydrofuran moiety with different heterocycles such as β-
lactams and sugars allows high levels of skeletal diversity.
INTRODUCTION
■
Allenes are a class of compounds with two cumulative carbon−
carbon double bonds, which are versatile synthetic intermedi-
ates in organic synthesis.1 In particular, bis(allenols) have
recently emerged as useful building blocks.2 On the other hand,
metal-mediated reactions for constructing carbon−carbon
bonds through addition of propargyl halides to carbonyl
compounds have been the subject of a number of investigations
over the past two decades, by virtue of its synthetic usefulness
and mechanistic intrigue.3 The reaction of propargyl bromides
with metals has been proposed to generate an equilibrium
between the allenyl and propargyl organometallics,4 which
often results in poor regioselection in the final organic product,
because both organometallic species can react with the carbonyl
compound. Thus, an important synthetic goal is to tune the
regioselectivity toward either acetylenic or allenic products.5
Although many efforts have been made in these fields for
various types of propargyl bromides, the direct preparation of
bis(allenols) through one-pot carbonyl bis(allenylation) has not
been reported yet.6 The synthetic advantages of organometallic
reactions in aqueous media are due to the fact that many
reactive functional groups, such as hydroxy, amine, and
carboxylic functions, do not require the protection−depro-
tection protocol, and many water-soluble compounds do not
need to be converted into their derivatives. Besides, the unique
reactivity and selectivity of these processes that are not often
attained under dry conditions make them profitable in many
cases.7 Because indium has emerged as the metal of choice to
mediate a high number of transformations in aqueous media,
RESULTS AND DISCUSSION
■
First, 1,4-bis(3-bromoprop-1-ynyl)benzene 1 (1.0 mmol) was
treated with 2-(allyloxy)benzaldehyde 2a (2.0 mmol) in the
presence of indium in THF/H2O (1:1), leading to the
bis(allenol) 3a in 51% yield as a single regioisomer but as an
inseparable syn/anti mixture (1:1). No signal for methylene
protons was detected, indicating that no homopropargylic
Received: May 6, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo500993x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 1. Indium-Promoted Controlled Bis(allenylation) Reaction of Aromatic Aldehydes
a
Conditions: (i) In, THF/NH4Cl (aq. sat.) (1:5), rt; 3a: 24 h; 3b: 72 h. (ii) 2-(4-Chlorophenoxy)acetyl chloride, Et3N, DMAP, CH2Cl2, rt, 2 h; then
fractional crystallization. (iii) MeONa, MeOH, 0 °C, 30 min.
a
Scheme 2. Indium-Promoted Controlled Bis(allenylation) Reaction of Enantiopure Aldehydes
a
Conditions: (i) In, THF/NH4Cl (aq. sat.) (1:5), rt; 8a: 24 h; 8b: 72 h; 8c: 24 h; 8d: 48 h; 9: 24 h; 10: 24 h. PMP = 4-MeOC6H4.
alcohol was observed in this case. Worthy of note, no detectable
reaction was observed in anhydrous THF. Several attempts to
improve the yield of the bis(allenylation) reaction using
dibromide 1 in aqueous media, including addition of additives
(InCl3, HfCl4, BiCl3, and AgTfO), were unsuccessful.
Fortunatelly, the ionic strength enhancement of the reaction
solvent provided by the addition of ammonium chloride
resulted in an improved 67% yield for 3a (Scheme 1). This
B
dx.doi.org/10.1021/jo500993x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3. Possible Pathway for the Indium-Promoted Bis(allenylation) Reaction of Carbonyls
practical preparation encouraged us to investigate the additions
of dibromide 1 to various aldehydes and ketones. Con-
sequently, the direct bis(allenylation) reaction of 2-(allyloxy)-5-
chlorobenzaldehyde 2b was conducted in the solvent system
THF/NH4Cl (aq. sat.) (1:5).12 The result in Scheme 1 shows
that the indium-mediated reaction is a good method for the
regioselective addition of bis(propargyl bromide) 1 to aromatic
aldehyde 2b, affording adducts 3b with complete regioselectiv-
ity. Despite the poor diastereoselectivity, adduct anti-3b was
obtained as a diastereomerically pure product after fractional
crystallization of its bis(4-chlorophenoxy)acetate anti-4. The
simplicity of the proton and carbon NMR spectra of adducts 3
points to their symmetrical nature.
could interconvert, but probably, in our case the isomerization
of propargylmetal to allenylmetal species is restricted by the
steric effect of the aryl substituent in the 1,4-bis(3-bromoprop-
1-ynyl)benzene derivative. The addition of the bis(propargyl-
indium) species to the carbonyl compound (aldehyde or
ketone), which probably proceeds via a double six-membered
cyclic transition state, leads to the corresponding bis(allenol)
after protodemetalation.
Since allenes possess a rich chemistry, the resulting
enantiopure coupled products are prone to undergo further
transformations, making them versatile synthetic tools. Since
annonaceous acetogenins are a large family of natural products
displaying several biological properties which contains a
bis(tetrahydrofuran) core, we decided to test a metal-catalyzed
double cyclization in our bis(allenes). To test the reactivity of
the bis(allenols), we started the initial investigation on the gold-
catalyzed reaction of bis(allene) 3b under AuCl3 catalysis.14
Interestingly, it was found that the 2-fold cyclization product
11b was exclusively formed in 72% yield (Scheme 4). Change
in the nature of the gold precatalyst has little effect on the
reaction, because replacing AuCl3 by Gagosz’ catalyst [(Ph3P)-
AuNTf2] did not show any appreciable difference. Con-
sequently, the much cheaper AuCl3 salt was used in the
following reactions. As shown in Schemes 4 and 5, differently
functionalized bis(dihydrofurans) 11−13 were smoothly
obtained in fair yields.
On the basis of the above gold-catalyzed results and keeping
in mind the importance of palladium-catalyzed chemistry for
the construction of several heterocycles by selective activation
of allenes, we screened the palladium-catalyzed 2-fold
cyclization coupling reaction of the challenging bis(allenolic)
β-lactam moiety with alkenyl halides. In the event, bis-
(dihydrofuryl-β-lactams) 14a,b and 15 were obtained (Scheme
6).
Macrocycles are essential structural features of biologically
relevant compounds, probably because large ring compounds
confer both stereochemical and conformational complexity to
the parent molecules.15 Among macrocycles, cyclophanes,
which are hydrocarbons consisting of an aromatic unit
(typically a benzene ring) and an aliphatic chain that forms a
The structure and stereochemistry of adduct anti-3b was
unambiguously assigned through the X-ray structure of its
bis(4-chlorophenoxy)acetate 4 (Figure S1, see the Supporting
Information).13
We were particularly interested in probing the degree of
reagent versus substrate regio- and stereocontrol in such
reactions with relevant classes of nonracemic aliphatic carbonyl
compounds. Thus, we evaluated the feasibility of the indium-
mediated Barbier-type carbonyl bis(allenylation) reactions of
azetidine-2,3-diones 5a−d, tetrahydrofuro[3,2-d][1,3]dioxole-
5-carbaldehyde 6, and 4-oxoazetidine-2-carbaldehyde 7 in eco-
friendly media, studying the diastereochemistry (syn vs anti)
and the regiochemistry of the connection (e.g., allenylation vs
propargylation). The regioselectivity was totally in favor of the
bis(cumulene) moiety. It was found that for α-keto lactams 5
these bis(additions) proceed with full diastereoselectivity
(Scheme 2), because the group at C4 was able to control the
stereochemistry of the new C3-substituted C3-hydroxy
quaternary center in bis(allenes) 8a−d. Bis(allenol) 9 arising
from enantiopure sugar derivative 6 was obtained in fair yield as
a mixture of chromatographically separable syn/anti isomers
(Scheme 2). The reaction of β-lactam carbaldehyde 7 afforded
bis(allenol) 10 as single isomer (Scheme 2).
A plausible mechanism for the bis(allenylation) process is
illustrated in Scheme 3. Initially, indium reacts with the
bis(halide) to form the bis(allenyl/propargyl organometallic).
The two organometallic reagents (allenyl and propargyl metal)
C
dx.doi.org/10.1021/jo500993x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 4. Gold-Catalyzed Double Cycloetherification
Reaction of Racemic Bis(allenols) 3
Scheme 6. Palladium-Catalyzed Double Cycloetherification−
a
Functionalization Reaction of Enantiopure Bis(allenols) 8a,b
a
and 10
a
Conditions: (i) 5 mol % AuCl3, CH2Cl2, rt, 2 h.
a
Conditions: (i) 5 mol % PdCl2, allyl bromide, DMF, rt; 14a: 3 h;
14b: 4 h; 15: 24 h.
Scheme 5. Gold-Catalyzed Double Cycloetherification
Reaction of Enantiopure Bis(allenols) 8c,d and 9
a
attention for preparation of macrocycles starting from tetraene
precursors 11 through the use of ruthenium-based carbenes.
RCM reactions were tested with Grubbs’ first generation
catalyst Ru-I, or Grubbs’ second generation catalyst Ru-II, or
Hoveyda−Grubbs’ second generation catalyst Ru-III (Figure 1)
Figure 1. Structures of carbenes Ru-I, Ru-II, and Ru-III.
in dichloromethane under high dilution conditions at reflux
temperature under argon atmosphere. To sustain sufficient
quantities of catalyst during the reaction progress, the carbene
was added in four portions (a total accumulated quantity of 10
mol %) in 1 h intervals. The RCM reaction of 11a (syn/anti =
1:1) was accomplished first by treatment with a catalytic
amount of Ru-II catalyst. The desired cyclophane 16a was
isolated as the sole product (inseparable mixture of isomers
syn/anti = 1:1) in quantitative yield. Worthy of note, the
macrocyclization reaction was totally stereoselective, with the Z
isomer being exclusively obtained (Scheme 7). Happily, the
bis(dihydrofuran) moiety remained untouched. A similar result
was obtained for the RCM of 11b (syn/anti = 1:1). Separating
the isomers obtained from salicylaldehyde derivatives was not
an easy task. Notably, we successfully isolated compounds syn-
16b and anti-16b in pure forms by subjecting the mixture of
diastereomers to repetitive column chromatography. The
stereochemistry of adducts syn-16b and anti-16b was
unambiguously assigned based on the RCM reaction of
isomerically pure anti-11b which afforded isomerically pure
syn-16b (Scheme 7).
a
Conditions: (i) 5 mol % AuCl3, CH2Cl2, rt; 12a: 3 h; 12b: 3 h; syn-
13: 3 h; anti-13: 4 h.
bridge between two nonadjacent positions of the aromatic ring,
have been recognized as catalysts and molecular receptors.16
Accordingly, we planned a ring closing metathesis (RCM)
strategy for obtaining bis(dihydrofuryl) cyclophanes. While the
RCM of dienes is well documented, that of polyenes has been
much less studied. Furthermore, the RCM studies of polyenes
were generally confined to those having a low degree of
substitution and functionalization. We initially focused our
Carbohydrates embedded in large macrocycles are relevant
entities because of their specific biological activities17 and
D
dx.doi.org/10.1021/jo500993x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 7. Ruthenium-Catalyzed RCM Macrocyclization Reaction of Racemic Dienyl Bis(dihydrofurans) 11
a
Conditions: (i) 10 mol % Ru-II or Ru-III, CH2Cl2 (high dilution conditions), reflux, 24 h.
Scheme 8. Ruthenium-Catalyzed RCM Macrocyclization Reaction of Enantiopure Sugar-Based Dienyl Bis(dihydrofuran) syn-
a
13
a
Conditions: (i) 10 mol % Ru-III, CH2Cl2 (high dilution conditions), reflux, 24 h. (ii) 10 mol % Ru-II, CH2Cl2 (high dilution conditions), reflux, 24
h.
chemical properties,18 such as their application in bioorganic
and supramolecular chemistry. Our synthetic approach to these
skeletons make use of sugar-based adducts 13. We subjected
dienes syn-13 and anti-13 to RCM reaction under similar
conditions as in the case of salicylaldehyde-derived dienes 11.
An attempted RCM reaction of anti-13 with ruthenium-based
carbenes was not successful. To our delight, encouraging results
were obtained using the epimeric adduct syn-13. It is interesting
to note that glycocyclophane 17 was obtained as a 3:2 mixture
of E- and Z-isomers using Ru-III (Scheme 8). Fortunately, the
E- and Z-isomers were chromatographically separable, which
allows the isolation of the thermodynamically less stable Z-
alkene. Interestingly, the RCM reaction of syn-13 catalyzed by
Ru-II was totally stereoselective because the sugar-based
macrocycle E-17 was isolated as the sole isomer (Scheme 8).
In addition to being the key structural motif in biologically
relevant compounds such as antibiotics and enzyme inhib-
itors,19 the β-lactam moiety is a versatile building block in
organic synthesis.20 Although the metathesis reaction is known
to be a powerful tool for the preparation of macrocycles, in the
E
dx.doi.org/10.1021/jo500993x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 9. Ruthenium-Catalyzed RCM Macrocyclization Reaction of Enantiopure β-Lactam-Based Dienyl Bis(dihydrofuran)
a
12a
a
Conditions: (i) 10 mol % Ru-II, CH2Cl2 (high dilution conditions), reflux, 24 h.
Scheme 10. Ruthenium-Catalyzed RCM Macrocyclization Reaction of Enantiopure β-Lactam-Based Dienyl Bis(dihydrofuran)
a
12b
a
Conditions: (i) 10 mol % Ru-I, CH2Cl2 (high dilution conditions), reflux, 24 h. (ii) 10 mol % Ru-II or Ru-III, CH2Cl2 (high dilution conditions),
reflux, 24 h.
field of β-lactam chemistry, only a few syntheses of macrocyclic
β-lactams have been reported based on RCM.21 Initially, dienyl
β-lactam 12a was selected as a model substrate for the RCM.
While the reaction of 12a under Ru-I catalysis afforded poor
results, the Ru-II-catalyzed reaction was extremely clean giving
rise to macrocyclic bis(β-lactam) E-18 in almost quantitative
yield as a single E-isomer (Scheme 9). The structure of the
macrocycle compound E-18 was determined by NMR, COSY,
and NOESY experiments (300 MHz) and confirmed by the
HRESI mass spectra of the molecular ion C32H36N2O8 [M]+ at
m/z 576.2448.
Having gained stereodefined access to the macrocycle 18
from 12a, we turned our attention to the conversion of the
homologue precursor 12b to the corresponding macrocyclic
derivative. To carry out the macrocyclization reaction, 12b was
subjected to RCM conditions. Nicely, Ru-I catalysis led to the
formation of the single isomer Z-19 in an excellent 84% yield
(Scheme 10). Z-Selectivity via RCM reaction is challenging
since the majority of catalysts prefer the thermodynamically
favored E-olefin.22 The RCM reaction of the diene derivative
12b, under otherwise identical conditions but catalyzed either
by Ru-II or Ru-III, furnished the desired β-lactam-cyclophane
19 as the sole product (mixture of isomers E/Z = 3:1;
nonseparable by flash chromatography) in quantitative yield
(Scheme 10). Fortunately, after fractional crystallization a small
amount of adduct E-19 was obtained as an isomerically pure
product for X-ray analysis (Figure S2; see the Supporting
Information).23
Gratifyingly, the scope of the macrocyclization process was
extended from O- or N-tethered dienes to C-tethered dienes by
using precursors 14 (Scheme 11). The reaction proceeded
smoothly with diene 14a to exclusively afford 12-membered
cyclophane Z-20a in good yield (71%). On the other hand,
with the diene 14b employed, a reaction mixture of cyclophane
Z-20b and nonmacrocyclized adduct 21 was obtained. The
pure macrocycle Z-20b was prepared in low overall yield as a
single Z-isomer according to NMR spectroscopy. It was also
possible to isolate pure isomerized diene 21 by column
chromatography.24 Probably, the obtention of the Z-alkenes Z-
20a and Z-20b as the sole isomers arises from the fact that the
small size of the macrocyclic cyclophane makes the formation
of the E-isomer difficult due to ring strain.
Diene 15 was found to be completely ineffective in carrying
out the requisite macrocyclization. Exposure of compound 15
to the ruthenium carbenes under our standard reaction
conditions resulted in clean formation of the open-chain
F
dx.doi.org/10.1021/jo500993x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 11. Ruthenium-Catalyzed RCM Macrocyclization
CONCLUSION
■
Reaction of Enantiopure β-Lactam-Based Dienyl
In conclusion, a straightforward metal-mediated method for the
synthesis of structurally different bis(dihydrofuryl) cyclophane
scaffolds from carbonyl compounds has been developed. The
process comprises indium-promoted one-pot carbonyl bis-
(allenylation) as well as gold- and palladium-catalyzed double
cyclization in the resulting bis(allenols), followed by selective
ruthenium-catalyzed macrocyclization.
a
Bis(dihydrofurans) 14
EXPERIMENTAL SECTION
■
General Methods. NMR spectra were recorded at 25 °C on a 700
or 300 MHz spectrometer. NMR spectra were recorded in CDCl3
solutions, unless stated otherwise. Chemical shifts are given in ppm
relative to TMS (1H, 0.0 ppm) or CDCl3 (13C, 76.9 ppm). Low and
high resolution mass spectra were acquired on a QTOF LC−MS
spectrometer using the electronic impact (EI) or electrospray modes
(ES). Specific rotation [α]D is given in 10−1 deg cm2 g−1 at 20 °C, and
the concentration (c) is expressed in g per 100 mL.
Indium-Promoted Reaction between 1,4-Bis(3-bromoprop-
1-ynyl)benzene 1 and Carbonyl Compounds. General Proce-
dure for the Synthesis of Bis(allenols) 3, 8−10. 1,4-Bis(3-
bromoprop-1-ynyl)benzene 1 (0.5 mmol) was added to a well stirred
suspension of the corresponding aldehyde or ketone (1.0 mmol) and
indium powder (6.0 mmol) in THF/NH4Cl (aq. sat.) (1:5, 12 mL) at
0 °C. The reaction mixture was stirred at room temperature. After
disappearance of the starting material (TLC) the mixture was
extracted with ethyl acetate (3 × 5 mL). The organic extract was
washed with brine, dried (MgSO4), and concentrated under reduced
pressure. Chromatography of the residue using ethyl acetate/hexanes
mixtures gave analytically pure compounds. Spectroscopic and
analytical data for bis(allenols) 3, 8−10 follow.
a
Conditions: (i) 10 mol % Ru-II or Ru-III, CH2Cl2 (high dilution
conditions), reflux, 24 h.
monoisomerization adduct 22 (Scheme 12). The sterically
more favored (E) configuration of the isomerizated double
bond was established by 1H NMR spectroscopy (J = 16.0 Hz).
Scheme 12. Ruthenium-Catalyzed Monoisomerization
Reaction of Enantiopure β-Lactam-Based Dienyl
Bis(dihydrofuran) 15
a
Bis(allenol) 3a. From 117 mg (0.86 mmol) of aldehyde 2a, and
after chromatography of the residue using hexanes/ethyl acetate (4:1)
as eluent, an inseparable syn/anti mixture (1:1) of compound 3a (137
mg, 67%) as a yellow oil was obtained; 1H NMR (300 MHz, C6D6, 25
°C) δ: 7.70 (s, 4H), 7.60 (dd, 2H, J = 8.8, 1.5 Hz), 7.17 (td, 2H, J =
7.0, 1.6 Hz), 6.99 (t, 2H, J = 7.5 Hz), 6.64 (d, 2H, J = 8.2 Hz), 6.30 (br
s, 2H), 5.78 (m, 2H), 4.17 (d, 4H, J = 5.0 Hz), 5.26 (d, 2H, J = 17.3
Hz), 5.06 (dt, 2H, J = 10.6, 1.5 Hz), 4.91 (m, 4H); 13C NMR (75
MHz, CDCl3, 25 °C) δ: 208.1, 156.0, 133.0, 131.6, 130.3, 128.8, 128.1,
126.7, 120.9, 117.5, 112.0, 109.2, 80.8, 80.7, 69.0, 68.3, 68.2; IR
(CHCl3) ν = 3340, 1963, 1226; HRMS (ES): calcd for C32H30O4
[M]+: 478.2144; found: 478.2157.
a
Conditions: (i) 10 mol % Ru-II or Ru-III, CH2Cl2 (high dilution
Bis(allenol) 3b. From 300 mg (1.52 mmol) of aldehyde 2b, and
after chromatography of the residue using hexanes/ethyl acetate (4:1)
as eluent, an inseparable syn/anti mixture (1:1) of compound 3b (144
conditions), reflux, 24 h.
1
mg, 35%) as a yellow oil was obtained; H NMR (300 MHz, CDCl3,
25 °C) δ: 7.36 (s, 4H), 7.35 (d, 2H, J = 2.7 Hz), 7.17 (dd, 2H, J = 8.7,
2.6 Hz), 6.79 (d, 2H, J = 8.8 Hz), 6.00 (m, 2H), 6.00 (m, 2H), 5.37
(dt, 2H, J = 17.2, 1.6 Hz), 5.27 (dt, 2H, J = 10.7, 1.3 Hz), 5.17 (qd,
4H, J = 12.4, 2.6 Hz), 4.56 (dd, 4H, J = 5.0, 1.1 Hz); 13C NMR (75
MHz, CDCl3, 25 °C) δ: 207.9 (2C), 154.4 (2C), 132.8, 132.8, 132.6
(2C) 132.2 (2C), 128.4 (2C), 127.8 (2C), 126.7 (4C), 125.8 (C),
117.8 (2C), 113.2 (2C), 108.8 (2C), 81.3 (2C), 81.2 (2C), 69.2 (2C),
67.4 (2C), 67.4 (2C); IR (CHCl3) ν = 3380, 1938, 1243; HRMS
(ES): calcd for C32H28O4Cl2 [M]+: 546.1344; found: 546.1365.
Bis(allenol) (+)-8a. From 100 mg (0.34 mmol) of ketone (+)-5a,
and after chromatography of the residue using hexanes/ethyl acetate
(4:1) as eluent, compound (+)-8a (61 mg, 48%) as a pale brown solid
was obtained; mp 128−129 °C; [α]D = +19.0 (c = 0.3 in CHCl3); 1H
NMR (300 MHz, CDCl3, 25 °C) δ: 7.63 (s, 4H), 7.56 (d, 4H, J = 9.0
Hz), 6.82 (d, 4H, J = 9.1 Hz), 5.27 (s, 4H), 4.51 (m, 4H), 4.40 (d, 2H,
J = 7.0 Hz), 4.26 (dd, 2H, J = 8.9, 6.7 Hz), 1.46 (s, 6H), 3.78 (s, 6H),
1.35 (s, 6H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 208.1 (2C), 166.2
(2C), 156.7 (2C), 131.9 (2C), 130.7 (2C), 128.5 (4C), 120.2 (4C),
114.0 (4C), 109.8 (2C), 105.7 (2C), 84.2 (2C), 80.9 (2C), 76.5 (2C),
66.8 (2C), 66.6 (2C), 55.4 (2C), 26.4 (2C), 25.2 (2C); IR (CHCl3) ν
The E- versus Z-stereochemistry of the metathesis-formed
double bonds could not be assigned taking into consideration
the usual coupling constants criteria. Fortunately, the chemical
shifts of the two olefinic protons located at the macrocyclic
double bond were diagnostic of the geometry of these
unsaturations. The signals for isomers 16a, syn-16b, anti-16b,
Z-17, Z-19, Z-20a, and Z-20b appeared approximately at 5.5
ppm, which suggests a Z-stereochemistry, whereas these
chemical shifts for adducts E-17, E-18, and E-19 are around
4.5 ppm and indicate an E-stereochemistry. These trends in
chemical shift may be explained based on the degree of
shielding or deshielding. Probably, the double bond of E-
isomers is located above of the benzene cone-shaped shielding
zone, forcing the signal to appear at higher field (lower
chemical shift). This configurational assignment was confirmed
by means of the X-ray diffraction analysis of the adduct E-19.
G
dx.doi.org/10.1021/jo500993x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
= 3321, 1955, 1740, 1198; HRMS (ES): calcd for C42H44N2O10 [M]+:
736.2996; found: 736.3000.
68.2, 26.9, 26.8, 26.4, 26.3; IR (CHCl3) ν = 3471, 1937, 1073, 1016;
HRMS (ES): calcd for C34H42O10 [M]+: 610.2778; found: 610.2789.
Bis(allenol) (+)-10. From 140 mg (0.89 mmol) of aldehyde (+)-7,
and after chromatography of the residue using hexanes/ethyl acetate
(3:1) as eluent, compound (+)-10 (140 mg, 53%) as a yellow oil was
Bis(allenol) (−)-8b. From 250 mg (0.91 mmol) of ketone (−)-5b,
and after chromatography of the residue using hexanes/ethyl acetate
(5:1) as eluent, compound (−)-8b (333 mg, 52%) as a yellow oil was
1
1
obtained; [α]D = −55.1 (c = 0.5 in CHCl3); H NMR (300 MHz,
obtained; [α]D = +10.8 (c = 0.5 in CHCl3); H NMR (300 MHz,
CDCl3, 25 °C) δ: 7.53 (s, 4H), 7.21 (m, 10H), 5.15 (d, 2H, J = 12.5
Hz), 5.06 (d, 2H, J = 12.5 Hz), 4.91 (d, 2H, J = 14.8 Hz), 4.47 (dt, 2H,
J = 6.7, 5.4 Hz), 4.15 (d, 2H, J = 14.8 Hz), 4.14 (dd, 4H, J = 8.9, 7.0
Hz), 3.68 (d, 2H, J = 6.7 Hz), 3.64 (dd, 2H, J = 9.7, 6.7 Hz), 1.37 (s,
6H), 1.35 (s, 6H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 207.5 (2C),
169.9 (2C), 135.2 (2C), 131.9 (2C), 128.6 (4C), 128.5 (4C), 128.4
(4C), 127.6 (2C), 109.9 (2C), 105.2 (2C), 84.9 (2C), 80.5 (2C), 75.8
(2C), 66.6 (2C), 64.4 (2C), 44.8 (2C), 26.4 (2C), 25.0 (2C); IR
(CHCl3) ν = 3316, 1937, 1732, 1211; HRMS (ES): calcd for
C42H44N2O8 [M]+: 704.3098; found: 704.3096.
CDCl3, 25 °C) δ: 7.30 (s, 4H), 7.28 (m, 10H), 5.17 (t, 4H, J = 1.9
Hz), 4.90 (brs, 2H), 4.80 (d, 2H, J = 15.1 Hz), 4.46 (d, 2H, J = 4.8
Hz), 4.32 (d, 2H, J = 15.1 Hz), 3.91 (dd, 2H, J = 6.0, 5.0 Hz), 3.53 (s,
6H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 207.6 (2C), 167.9 (2C),
135.8 (2C), 132.9 (2C), 128.7 (4C), 128.1 (4C), 127.6 (2C), 126.9
(4C), 106.6, 83.6, 80.8, 68.9, 60.4, 59.7, 45.5; IR (CHCl3) ν = 3364,
1952, 1747; HRMS (ES): calcd for C36H36N2O6 [M]+: 592.2573;
found: 592.2569.
Procedure for the Bis(4-chlorophenoxy)acetylation of the
Syn/Anti Mixture (1:1) of Bis(allenol) 3b. Preparation of
bis(allenol) anti-3b. Triethylamine (2.2 mmol) and 2-(4-chloro-
phenoxy)acetyl chloride (0.87 mmol) were sequentially added
dropwise via syringe to a solution of bis(allenol) syn/anti-3b (402
mg, 0.73 mmol) and DMAP (cat) in dichloromethane (3 mL) at 0 °C
under argon. The resulting mixture was allowed to warm to room
temperature and then was stirred 2 h at room temperature. The crude
mixture was diluted with CH2Cl2 (8 mL) and washed with saturated
aqueous ammonium chloride (3 × 5 mL) and brine (3 × 5 mL). The
organic layer was dried (MgSO4) and concentrated under reduced
pressure. The mixture was purified by column chromatography eluting
with ethyl acetate/hexanes (1:9) and then by fractional crystallization
(ethyl acetate/hexanes) to give 172 mg (27%) of the more polar
compound bis(4-chlorophenoxy)acetate anti-4 and 213 mg of the
bis(4-chlorophenoxy)acetate syn-4 (4:1 syn/anti mixture).
Bis(4-chlorophenoxy)acetate anti-4. Colorless solid; mp 164−
166 °C; 1H NMR (300 MHz, CDCl3, 25 °C) δ: 7.29 (s, 4H), 7.28 (m,
4H), 7.21 (m, 2H), 7.19 (d, 4H, J = 8.9 Hz), 6.80 (d, 2H, J = 8.7 Hz),
6.76 (d, 4H, J = 9.0 Hz), 5.95 (ddt, 2H, J = 17.3, 10.3, 5.0 Hz), 5.34
(dt, 2H, J = 17.2, 1.5 Hz), 5.22 (dq, 2H, J = 10.7, 1.3 Hz), 5.16 (d, 4H,
J = 2.4 Hz), 4.62 (d, 4H, J = 1.3 Hz), 4.55 (d, 4H, J = 4.9 Hz); 13C
NMR (75 MHz, CDCl3, 25 °C) δ: 209.2 (2C), 167.6 (2C), 156.3
(2C), 154.2 (2C), 132.5 (4C), 129.4 (4C), 129.3 (2C), 128.2 (2C),
128.0 (2C), 126.7 (2C), 126.6 (4C), 125.7 (2C), 117.6 (2C), 116.0
(4C), 113.3 (2C), 105.9 (2C), 81.3 (2C), 69.3 (2C), 68.0 (2C), 65.5
(2C); IR (CHCl3) ν = 3321, 1941, 1762, 1174; HRMS (ES): calcd for
C48H38O8Cl4 [M]+: 882.1321; found: 882.1341.
Bis(allenol) (+)-8c. From 212 mg (0.94 mmol) of ketone (−)-5c,
and after chromatography of the residue using hexanes/ethyl acetate
(2:1) as eluent, compound (+)-8c (360 mg, 63%) as a yellow oil was
1
obtained; [α]D = +79.7 (c = 0.7 in CHCl3); H NMR (300 MHz,
CDCl3, 25 °C) δ: 7.56 (s, 4H), 5.61 (m, 2H), 5.20 (s, 4H), 5.17 (m,
4H), 4.62 (s, 2H), 4.20 (dd, 2H, J = 12.6, 6.8 Hz), 4.18 (m, 4H), 3.83
(d, 2H, J = 7.2 Hz), 3.68 (m, 4H), 1.41 (s, 6H), 1.35 (s, 6H); 13C
NMR (75 MHz, CDCl3, 25 °C) δ: 207.7 (2C), 168.9 (2C), 132.1
(2C), 131.4 (2C), 128.5 (4C), 118.4 (2C), 109.8 (2C), 105.6 (2C),
84.8 (2C), 80.4 (2C), 76.1 (2C), 66.7 (2C), 65.2 (2C), 45.5 (2C),
26.6 (2C), 25.1 (2C); IR (CHCl3) ν = 3329, 1943, 1727, 1210;
HRMS (ES): calcd for C34H40N2O8 [M]+: 604.2785; found: 604.2798.
Bis(allenol) (−)-8d. From 1 g (4.35 mmol) of ketone (−)-5d, and
after chromatography of the residue using hexanes/ethyl acetate (5:1)
as eluent, compound (−)-8d (594 mg, 45%) as a yellow oil was
1
obtained; [α]D = −14.9 (c = 0.6 in CHCl3); H NMR (300 MHz,
CDCl3, 25 °C) δ: 7.56 (s, 4H), 5.70 (ddt, 2H, J = 16.9, 10.2, 6.7 Hz),
5.20 (s, 4H), 5.04 (m, 4H), 4.46 (brs, 2H), 4.19 (dd, 2H, J = 8.8, 6.8
Hz), 4.42 (dd, 2H, J = 13.8, 6.6 Hz), 3.83 (d, 2H, J = 7.7 Hz), 3.67
(dd, 2H, J = 8.5, 5.9 Hz), 3.59 (m, 2H), 3.24 (dt, 2H, J = 13.8, 6.6 Hz),
2.34 (m, 4H), 1.44 (s, 6H), 1.36 (s, 6H); 13C NMR (75 MHz, CDCl3,
25 °C) δ: 207.7 (2C), 168.9 (2C), 134.9 (2C), 132.0 (2C), 128.5
(4C), 117.0 (2C), 109.6 (2C), 105.6 (2C), 84.4 (2C), 80.3 (2C), 76.4
(2C), 66.8 (2C), 65.5 (2C), 40.4 (2C), 31.7 (2C), 26.6 (2C), 25.1
(2C); IR (CHCl3) ν = 3308, 1938, 1733, 1067; HRMS (ES): calcd for
C36H44N2O8 [M]+: 632.3098; found: 632.3100.
Reaction of Aldehyde (−)-6. From 500 mg (2.20 mmol) of
aldehyde (−)-6 and chromatography of the residue using hexanes/
ethyl acetate (3:1) as eluent, 182 mg (26%) of the less polar
compound (−)-anti-9 and 146 mg (22%) of the more polar
compound (−)-syn-9 were obtained.
Bis(allenol) (−)-syn-9. Yellow oil; [α]D = −28.9 (c = 1.0 in
CHCl3); 1H NMR (300 MHz, CDCl3, 25 °C) δ: 1.33 (s, 6H), 1.50 (s,
6H), 2.64 (brs, 2H), 3.74 (ddt, 2H, J = 12.5, 6.3, 1.2 Hz), 3.89 (d, 2H,
J = 3.3 Hz), 3.99 (ddt, 2H, J = 12.5, 5.3, 1.3 Hz), 4.41 (dd, 2H, J = 8.1,
3.3 Hz), 4.57 (d, 2H, J = 3.7 Hz), 4.96 (d, 2H, J = 8.1 Hz), 5.13 (m,
4H), 5.22 (dd, 2H, J = 12.4, 1.2 Hz), 5.32 (dd, 2H, J = 12.4, 0.9 Hz),
5.63 (m, 2H), 5.99 (d, 2H, J = 3.7 Hz), 7.47 (s, 4H); 13C NMR (75
MHz, CDCl3, 25 °C) δ: 208.4 (2C), 133.6 (2C), 133.3 (2C), 126.8
(4C), 118.1 (2C), 112.0 (2C), 105.3 (2C), 104.9 (2C), 82.9 (2C),
82.6 (2C), 81.3 (2C), 80.6 (2C), 71.1 (2C), 68.3 (2C), 26.9 (2C),
26.4 (2C); IR (CHCl3) ν = 3473, 1937, 1073, 1015; HRMS (ES):
calcd for C34H42O10 [M]+: 610.2778; found: 610.2780.
Procedure for the Transesterification of the Bis(4-chloro-
phenoxy)acetate anti-4. Preparation of Bis(allenol) anti-3b.
Sodium methoxide (10 mg, 0.19 mmol) was added in portions at 0 °C
to a solution of the bis(4-chlorophenoxy)acetate anti-4 (172 mg, 0.19
mmol) in methanol (1.9 mL). The reaction was stirred for 30 min at 0
°C, and then water was added (1 mL). The methanol was removed
under reduced pressure, the aqueous residue was extracted with ethyl
acetate, and the organic layer was dried (MgSO4). The mixture was
concentrated under reduced pressure and was purified by column
chromatography eluting with ethyl acetate/hexanes (1:4) to give 82
mg (77%) of analytically pure bis(allenol) anti-3b.
1
Bis(allenol) anti-3b. Yellow oil; H NMR (300 MHz, CDCl3, 25
°C) δ: 7.36 (s, 4H), 7.35 (d, 2H, J = 2.6 Hz), 7.18 (dd, 2H, J = 8.7, 2.6
Hz), 6.80 (d, 2H, J = 8.8 Hz), 6.00 (m, 4H), 5.37 (dt, 2H, J = 17.3, 1.4
Hz), 5.27 (dt, 2H, J = 10.5, 1.2 Hz), 5.18 (qd, 4H, J = 12.3, 2.6 Hz),
4.56 (dt, 4H, J = 5.1, 1.5 Hz); 13C NMR (75 MHz, CDCl3, 25 °C) δ:
208.0 (2C), 154.5 (2C), 132.9, 132.6 (2C) 132.3 (2C), 128.5 (2C),
127.9 (2C), 126.8 (4C), 125.9, 117.8 (2C), 113.3 (2C), 109.0 (2C),
81.2 (2C), 69.4 (2C), 67.5 (2C); IR (CHCl3) ν = 3243, 1938, 1241;
HRMS (ES): calcd for C32H28O4Cl2 [M]+: 546.1344; found: 546.1365.
General Procedure for the Gold-Catalyzed Double Cyclo-
etherification Reaction of Bis(allenols) 3, 8, and 9. Preparation
of Compounds 11−13. AuCl3 (0.005 mmol) was added to a stirred
solution of the corresponding bis(allenol) 3, 8, or 9 (0.1 mmol) in
dichloromethane (1 mL) under argon. The resulting mixture was
stirred at room temperature until complete disappearance (TLC) of
the starting material. The reaction was then quenched with brine (0.2
mL), the mixture was extracted with ethyl acetate (3 × 5 mL), and the
Bis(allenol) (−)-anti-9. Yellow oil; [α]D = −27.7 (c = 0.8 in
1
CHCl3); H NMR (300 MHz, CDCl3, 25 °C) δ: 7.43 (m, 4H), 6.00
(d, 1H, J = 3.6 Hz), 5.99 (d, 1H, J = 5.9 Hz), 5.91 (m, 1H, CH=CH2),
5.61 (m, 1H), 1.31 (s, 3H), 5.35 (m, 2H), 5.28 (m, 4H), 5.14 (m, 2H),
4.94 (m, 1H), 4.57 (d, 2H, J = 3.6 Hz), 4.41 (dd, 1H, J = 8.1, 3.2 Hz),
4.33 (dd, 1H, J = 5.8, 3.4 Hz), 4.14 (d, 1H, J = 3.4 Hz), 4.00 (m, 1H),
3.89 (d, 1H, J = 3.3 Hz), 3.73 (m, 1H), 3.28 (brs, 1H), 2.65 (brs, 1H),
1.50 (s, 3H), 1.42 (s, 3H), 1.33 (s, 3H), 1.31 (s, 3H); 13C NMR (75
MHz, CDCl3, 25 °C) δ: 208.5, 208.2, 133.6, 133.4, 133.3, 133.1, 126.8
(2C), 126.4 (2C), 118.3, 118.1, 112.0, 111.7, 105.3, 105.0, 104.9,
104.9, 83.1, 82.9, 82.6 (2C), 81.9, 81.3, 80.9, 80.7, 71.1 (2C), 68.4,
H
dx.doi.org/10.1021/jo500993x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
combined extracts were washed twice with brine. The organic layer
was dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue eluting with ethyl acetate/hexanes
or acetate/dichloromethane mixtures gave analytically pure adducts
11−13.
(2C), 136.8 (2C), 134.9 (2C), 131.9 (2C), 127.4 (2C), 127.3 (4C),
117.0 (2C), 109.7 (2C), 99.4 (2C), 76.8 (2C), 76.0 (2C), 66.3 (2C),
65.8 (2C), 40.9 (2C), 31.7 (2C), 26.6 (2C), 24.7 (2C); IR (CHCl3) ν
= 1754, 1078; HRMS (ES): calcd for C36H44N2O8 [M]+: 632.3098;
found: 632.3108.
Dienyl Bis(dihydrofuran) 11a. From 152 mg (0.31 mmol) of
bis(allenol) 3a, and after chromatography of the residue using
hexanes/ethyl acetate (6:1) as eluent, compound 11a (83 mg, 47%) as
Dienyl Bis(dihydrofuran) (−)-syn-13. From 60 mg (0.10 mmol)
of bis(allenol) (−)-syn-9, and after chromatography of the residue
using hexanes/ethyl acetate (3:1) as eluent, compound (−)-syn-13 (33
mg, 61%) as a yellow oil was obtained; [α]D = −85.7 (c = 1.6 in
CHCl3); 1H NMR (300 MHz, CDCl3, 25 °C) δ: 7.31 (s, 4H), 6.16 (d,
2H, J = 1.7 Hz), 5.92 (m, 2H), 5.89 (d, 2H, J = 4.4 Hz), 5.54 (m, 2H),
5.34 (dd, 2H, J = 17.3, 1.6 Hz), 5.23 (dd, 2H, J = 10.5, 1.4 Hz), 4.85
(m, 4H), 4.65 (dd, 2H, J = 4.2, 1.7 Hz), 4.33 (dd, 2H, J = 5.4, 3.9 Hz),
4.12 (ddt, 2H, J = 13.0, 4.9, 1.5 Hz), 3.80 (dd, 2H, J = 5.5, 1.7 Hz),
3.75 (ddt, 2H, J = 13.0, 5.6, 1.4 Hz), 1.42 (s, 6H), 1.33 (s, 6H); 13C
NMR (75 MHz, CDCl3, 25 °C) δ: 139.2 (2C), 133.9 (2C), 132.9
(2C), 126.9 (4C), 124.9 (2C), 117.2 (2C), 112.6 (2C), 105.2 (2C),
84.1 (2C), 83.7 (2C), 82.9 (2C), 80.3 (2C), 75.6 (2C), 70.7 (2C),
27.4 (2C), 27.0 (2C); IR (CHCl3) ν = 1070, 1018; HRMS (ES): calcd
for C34H42O10 [M]+: 610.2778; found: 610.2765.
1
a yellow solid was obtained; mp 154−156 °C; H NMR (300 MHz,
CDCl3, 25 °C) δ: 7.10 (s, 4H), 7.10 (m, 4H), 6.79 (m, 4H), 6.55 (m,
2H), 6.33 (m, 2H), 6.01 (m, 2H), 5.35 (m, 2H), 5.20 (m, 2H), 4.81
(m, 4H), 4.53 (m, 4H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 156.1
(2C), 140.6 (2C), 140.5 (2C) 133.3 (2C) 132.0 (2C), 131.9 (2C),
129.2 (2C), 129.2 (2C), 129.2 (2C), 129.1 (2C), 128.6 (2C), 128.5
(2C), 126.4 (4C), 126.4 (4C), 122.8 (2C), 122.7 (2C), 121.1 (2C),
117.3 (2C), 117.3 (2C), 112.4 (2C), 112.3 (2C), 80.9 (2C), 80.8
(2C), 75.2 (2C), 69.2 (2C), 69.2 (2C); IR (CHCl3) ν = 1230; HRMS
(ES): calcd for C32H30O4 [M]+: 478.2144; found: 478.2143.
Dienyl Bis(dihydrofuran) 11b. From 190 mg (0.35 mmol) of
bis(allenol) 3b, and after chromatography of the residue using
hexanes/ethyl acetate (6:1) as eluent, compound 11b (136 mg, 72%)
as a colorless oil was obtained; 1H NMR (300 MHz, CDCl3, 25 °C) δ:
7.19 (s, 4H), 7.13 (m, 4H), 6.80 (d, 2H, J = 8.6 Hz), 6.79 (d, 2H, J =
8.5 Hz), 6.59 (m, 1H), 6.43 (q, 2H, J = 1.9 Hz), 6.40 (q, 2H, J = 1.9
Hz), 6.06 (m, 2H), 5.42 (m, 2H), 5.30 (m, 2H), 4.90 (m, 4H), 4.58
(m, 4H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 154.5 (2C), 140.4
(2C), 140.3 (2C), 132.8 (2C), 132.8 (2C), 131.9 (2C), 131.8 (2C),
131.3 (2C), 131.2 (2C), 129.0 (2C), 129.0 (2C), 128.4 (2C), 126.4
(4C), 126.4 (4C), 126.1 (2C), 126.0 (2C), 123.1 (2C), 123.0 (2C),
117.6 (2C), 113.7 (2C), 113.7 (2C), 80.4 (2C), 80.3 (2C), 75.4 (2C),
69.5 (2C), 69.5 (2C); IR (CHCl3) ν = 1247; HRMS (ES): calcd for
C32H28O4Cl2 [M]+: 546.1342; found: 546.1365.
Dienyl Bis(dihydrofuran) anti-11b. From 47 mg (0.09 mmol) of
bis(allenol) anti-3b, and after chromatography of the residue using
hexanes/ethyl acetate (6:1) as eluent, compound anti-11b (28 mg,
60%) as a colorless oil was obtained; 1H NMR (300 MHz, CDCl3, 25
°C) δ: 7.18 (s, 4H), 7.13 (m, 4H), 6.79 (d, 2H, J = 8.5 Hz), 6.59 (m,
2H), 6.40 (c, 2H, J = 1.8 Hz), 6.05 (m, 2H), 5.41 (dd, 2H, J = 17.3, 1.5
Hz), 5.30 (dd, 2H, J = 10.5, 1.3 Hz), 4.90 (m, 4H), 4.58 (m, 4H); 13C
NMR (75 MHz, CDCl3, 25 °C) δ: 154.6 (2C), 140.5 (2C), 132.9
(2C), 131.9 (2C), 131.4 (2C), 129.0 (2C), 128.5 (2C), 126.5 (4C),
126.1 (2C), 123.2 (2C), 117.7 (2C), 113.7 (2C), 80.5 (2C), 75.4
(2C), 69.6 (2C); IR (CHCl3) ν = 1247; HRMS (ES): calcd for
C32H28O4Cl2 [M]+: 546.1342; found: 546.1365.
Dienyl Bis(dihydrofuran) (+)-12a. From 86 mg (0.14 mmol) of
bis(allenol) (+)-8c, and after chromatography of the residue using
dichloromethane/ethyl acetate (9:1) as eluent, compound (+)-12a (60
mg, 69%) as a pale brown solid was obtained; mp 210−212 °C; [α]D =
+31.3 (c = 1.1 in CHCl3); 1H NMR (300 MHz, CDCl3, 25 °C) δ: 7.33
(s, 4H), 6.29 (t, 2H, J = 1.7 Hz), 5.69 (m, 2H), 5.16 (m, 4H), 4.97
(dd, 2H, J = 14.2, 1.8 Hz), 4.71 (dd, 2H, J = 14.2, 1.7 Hz), 4.42 (m,
2H), 4.22 (dd, 2H, J = 15.0, 5.7 Hz), 4.14 (dd, 2H, J = 8.4, 6.9 Hz),
3.80 (dd, 2H, J = 15.0, 7.2 Hz), 3.51 (d, 2H, J = 8.9 Hz), 3.48 (dd, 2H,
J = 8.5, 5.6 Hz), 1.35 (s, 6H), 1.32 (s, 6H); 13C NMR (75 MHz,
CDCl3, 25 °C) δ: 168.1 (2C), 137.0 (2C), 131.9 (2C), 130.7 (2C),
127.4 (4C), 127.3 (2C), 119.4 (2C), 109.8 (2C), 99.5 (2C), 76.9
(2C), 76.1 (2C), 66.3 (2C), 65.0 (2C), 44.1 (2C), 26.7 (2C), 24.8
(2C); IR (CHCl3) ν = 1741, 1248; HRMS (ES): calcd for
C34H40N2O8 [M]+: 604.2785; found: 604.2791.
Dienyl Bis(dihydrofuran) (−)-anti-13. From 65 mg (0.11 mmol)
of bis(allenol) (−)-anti-9, and after chromatography of the residue
using hexanes/ethyl acetate (3:1) as eluent, compound (−)-anti-13
(32 mg, 50%) as a yellow oil was obtained; [α]D = −44.5 (c = 1.3 in
1
CHCl3); H NMR (300 MHz, CDCl3, 25 °C) δ: 7.45 (d, 2H, J = 8.3
Hz), 7.28 (d, 2H, J = 8.1 Hz), 6.23 (d, 1H, J = 1.4 Hz), 6.13 (d, 1H, J
= 1.7 Hz), 5.97 (m, 2H), 5.90 (d, 1H, J = 4.0 Hz), 5.86 (d, 1H, J = 4.3
Hz), 5.54 (m, 2H), 5.35 (m, 2H), 5.23 (m, 2H), 4.80 (m, 4H), 4.63
(dd, 1H), 4.51 (d, 1H, J = 3.8 Hz), 4.32 (t, 1H, J = 4.8 Hz), 4.18 (m,
2H), 4.12 (dd, 1H, J = 8.3, 3.1 Hz), 4.07 (m, 1H), 3.99 (d, 1H, J = 3.0
Hz), 3.75 (m, 1H), 3.74 (dd, 1H, J = 5.3, 1.4 Hz), 1.43 (s, 3H), 1.40
(s, 3H), 1.32 (s, 3H), 1.27 (s, 3H); 13C NMR (75 MHz, CDCl3, 25
°C) δ: 141.4, 139.5, 134.4, 134.2, 132.8, 132.6, 127.0 (2C), 126.6
(2C), 124.8, 123.7, 117.5, 117.0, 112.5, 111.3, 105.3, 105.2, 83.8, 83.7,
82.7, 82.4, 82.1, 82.0, 81.4, 80.5, 75.5, 75.1, 71.6, 70.5, 27.3, 27.0, 26.7,
26.1; IR (CHCl3) ν = 1071, 1014; HRMS (ES): calcd for C34H42O10
[M]+: 610.2778; found: 610.2801.
General Procedure for the Palladium-Catalyzed Double
Cyclization/Cross-Coupling Reaction of Bis(allenols) 8 and 10.
Preparation of Compounds 14 and 15. Palladium(II) chloride
(0.005 mmol) was added to a stirred solution of the corresponding
bis(allenol) 8 or 10 (0.10 mmol) and allyl bromide (0.50 mmol) in
N,N-dimethylformamide (0.6 mL). The reaction was stirred under an
argon atmosphere until disappearance of the starting material (TLC).
Water (0.5 mL) was added before being extracted with ethyl acetate (3
× 4 mL). The organic phase was washed with water (2 × 2 mL), dried
(MgSO4), and concentrated under reduced pressure. Chromatography
of the residue eluting with hexanes/ethyl acetate mixtures gave
analytically pure adducts 14 and 15.
Dienyl Bis(dihydrofuran) (+)-14a. From 50 mg (0.07 mmol) of
bis(allenol) (+)-8a, and after chromatography of the residue using
hexanes/ethyl acetate (3:1) as eluent, compound (+)-14a (34 mg,
59%) as a pale brown solid was obtained; mp 199−202 °C; [α]D
=
+53.6 (c = 0.9 in CHCl3); 1H NMR (300 MHz, CDCl3, 25 °C) δ: 7.51
(d, 4H, J = 9.1 Hz), 7.16 (s, 4H), 6.81 (d, 4H, J = 9.1 Hz), 5.74 (ddt,
2H, J = 16.6, 10.2, 6.4 Hz), 5.09 (m, 2H), 5.04 (m, 2H), 4.89 (d, 2H, J
= 13.4 Hz), 4.72 (d, 2H, J = 13.4 Hz), 4.44 (dt, 2H, J = 8.8, 6.6 Hz),
4.25 (dd, 2H, J = 8.4, 7.2 Hz), 3.77 (s, 6H), 3.71 (d, 2H, J = 8.5 Hz),
3.53 (dd, 2H, J = 8.4, 6.5 Hz), 2.89 (m, 4H), 1.37 (s, 6H), 1.30 (s,
6H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 166.2 (2C), 156.6 (2C),
138.6 (2C), 133.7 (2C), 131.3 (2C), 130.9 (2C), 130.4 (2C), 129.0
(4C), 119.9 (4C), 117.2, 113.9 (4C), 109.8 (2C), 101.0 (2C), 78.4
(2C), 76.9 (2C), 66.8 (2C), 66.4 (2C), 55.3 (2C), 30.3 (2C), 26.4
(2C), 24.6 (2C); IR (CHCl3) ν = 1739, 1220; HRMS (ES): calcd for
C48H52N2O10 [M]+: 816.3622; found: 816.3614.
Dienyl Bis(dihydrofuran) (+)-12b. From 130 mg (0.107 mmol)
of bis(allenol) (−)-8d, and after chromatography of the residue using
hexanes/ethyl acetate (3:1) as eluent, compound (+)-12b (90 mg,
70%) as a colorless solid was obtained; mp 234−235 °C; [α]D = +21.0
1
(c = 0.2 in CHCl3); H NMR (300 MHz, CDCl3, 25 °C) δ: 7.34 (s,
4H), 6.29 (t, 2H, J = 1.7 Hz), 5.70 (ddt, 2H, J = 16.9, 10.2, 6.7 Hz),
5.00 (m, 4H), 4.96 (dd, 2H, J = 14.1, 1.6 Hz), 4.70 (dd, 2H, J = 14.3,
1.7 Hz), 4.40 (ddd, 2H, J = 8.9, 6.7, 6.0 Hz), 4.15 (dd, 2H, J = 8.4, 6.9
Hz), 3.57 (dt, 2H, J = 13.1, 7.1 Hz), 3.53 (d, 2H, J = 8.8 Hz), 3.47 (dd,
2H, J = 8.5, 5.9 Hz), 3.39 (dt, 2H, J = 13.9, 6.7 Hz), 2.35 (m, 4H), 1.37
(s, 6H), 1.33 (s, 6H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 168.4
Dienyl Bis(dihydrofuran) (+)-14b. From 300 mg (0.42 mmol) of
bis(allenol) (−)-8b, and after chromatography of the residue using
hexanes/ethyl acetate (5:1) as eluent, compound (+)-14b (150 mg,
45%) as a colorless solid was obtained; mp 186−187 °C; [α]D = +86.1
(c = 1.6 in CHCl3); 1H NMR (300 MHz, CDCl3, 25 °C) δ: 7.12 (m,
I
dx.doi.org/10.1021/jo500993x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
10H), 6.96 (s, 4H), 5.77 (ddt, 2H, J = 16.4, 10.2, 6.2 Hz), 5.13 (m,
2H), 5.07 (m, 2H), 4.86 (d, 2H, J = 13.4 Hz), 4.78 (d, 2H, J = 14.5
Hz), 4.70 (d, 2H, J = 13.3 Hz), 4.45 (dt, 2H, J = 8.9, 6.4 Hz), 4.19 (d,
2H, J = 14.3 Hz), 4.17 (m, 2H), 3.47 (dd, 2H, J = 8.3, 6.1 Hz), 3.24 (d,
2H, J = 8.9 Hz), 2.87 (qd, 4H, J = 15.8, 6.2 Hz), 1.35 (s, 6H), 1.33 (s,
6H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 168.3 (2C), 138.1 (2C),
135.0 (2C), 134.0 (2C), 130.9 (2C), 130.8 (2C), 128.8 (4C), 128.6
(4C), 128.2 (4C), 127.5 (2C), 117.0, 109.6 (2C), 101.6 (2C), 78.2,
76.9 (2C), 66.3 (2C), 64.5 (2C), 45.2 (2C), 30.2 (2C), 26.4 (2C),
24.5 (2C); IR (CHCl3) ν = 1752, 1208; HRMS (ES): calcd for
C48H52N2O8 [M]+: 784.3724; found: 784.3754.
Reaction of Dienyl Bis(dihydrofuran) 11b. From 40 mg (0.073
mmol) of dienyl bis(dihydrofuran) 11b (syn/anti = 1:1), and after
chromatography of the residue using hexanes/ethyl acetate (6:1) as
eluent, 9 mg (24%) of the less polar compound anti-16b and 10 mg
(27%) of the more polar compound syn-16b were obtained.
Cyclophane anti-16b. Colorless solid; mp 214−215 °C; 1H NMR
(300 MHz, CDCl3, 25 °C) δ: 7.29 (d, 2H, J = 2.7 Hz), 7.22 (s, 4H),
7.13 (dd, 2H, J = 8.8, 2.7 Hz), 6.69 (d, 2H, J = 8.8 Hz), 6.51 (ddd, 1H,
J = 5.7, 3.5, 2.0 Hz), 6.27 (q, 2H, J = 1.7 Hz), 5.90 (m, 2H), 5.11 (ddd,
2H, J = 13.8, 6.0, 1.7 Hz), 4.90 (ddd, 2H, J = 13.8, 3.5, 2.0 Hz), 4.71
(m, 4H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 152.7 (2C), 142.4
(2C), 133.2 (2C), 132.1 (2C), 128.7 (2C), 128.6 (2C), 128.5 (2C),
126.6 (4C), 126.1 (2C), 121.9 (2C), 112.5 (2C), 80.5 (2C), 76.2
(2C), 67.4 (2C); IR (CHCl3) ν = 1248; HRMS (ES): calcd for
C30H24O4Cl2 [M]+: 518.1073; found: 518.1052.
Dienyl Bis(dihydrofuran) (+)-15. From 190 mg (0.31 mmol) of
bis(allenol) (+)-10, and after chromatography of the residue using
hexanes/ethyl acetate (3:1) as eluent, compound (+)-15 (81 mg, 39%)
1
as colorless oil was obtained; [α]D = +17.3 (c = 0.7 in CHCl3); H
Cyclophane (−)-E-17. From 73 mg (0.11 mmol) of dienyl
bis(dihydrofuran) (−)-syn-13, and after chromatography of the residue
using hexanes/ethyl acetate (3:1) as eluent, compound (−)-E-17 (26
mg, 40%) as a colorless oil was obtained; [α]D = −8.6 (c = 3.2 in
CHCl3); 1H NMR (300 MHz, CDCl3, 25 °C) δ: 7.41 (s, 4H), 6.14 (d,
2H, J = 1.3 Hz), 5.91 (d, 2H, J = 3.8 Hz), 5.54 (m, 2H), 4.82 (m, 4H),
4.72 (brs, 2H), 4.52 (d, 2H, J = 3.8 Hz), 4.24 (dd, 2H, J = 6.6, 2.7 Hz),
4.01 (d, 2H, J = 14.1 Hz), 3.81 (d, 2H, J = 14.4 Hz), 3.70 (d, 2H, J =
2.8 Hz), 1.52 (s, 6H), 1.31 (s, 6H); 13C NMR (75 MHz, CDCl3, 25
°C) δ: 141.2 (2C), 133.3 (2C), 127.1 (4C), 126.8 (2C), 125.2 (2C),
111.5 (2C), 103.9 (2C), 83.3, 82.3, 80.2 (2C), 78.7 (2C), 74.0 (2C),
67.0 (2C), 26.7 (2C), 26.2 (2C); IR (CHCl3) ν = 1075, 1020; HRMS
(ES): calcd for C32H38O10 [M]+: 582.2465; found: 582.2468.
Reaction of Dienyl Bis(dihydrofuran) (−)-syn-13. From 80 mg
(0.13 mmol) of dienyl bis(dihydrofuran) (−)-syn-13, and after
chromatography of the residue using hexanes/ethyl acetate (3:1) as
eluent, 24 mg (30%) of the less polar compound (−)-E-17 and 15 mg
(20%) of the more polar compound (−)-Z-17 were obtained.
Cyclophane (−)-Z-17. Colorless oil; [α]D = −38.4 (c = 0.43 in
CHCl3); 1H NMR (300 MHz, CDCl3, 25 °C) δ: 7.24 (s, 4H), 6.00 (d,
2H, J = 1.6 Hz), 5.73 (d, 2H, J = 3.7 Hz), 5.53 (m, 2H), 5.23 (brs,
2H), 4.78 (m, 4H), 4.27 (d, 2H, J = 3.7 Hz), 4.18 (dd, 2H, J = 6.0, 2.6
Hz), 1.28 (s, 6H), 3.62 (d, 2H, J = 12.1 Hz), 3.34 (d, 2H, J = 2.5 Hz),
3.07 (d, 2H, J = 14.0 Hz), 1.48 (s, 6H); 13C NMR (75 MHz, CDCl3,
25 °C) δ: 141.5 (2C), 133.3 (2C), 127.2 (4C), 126.5 (2C), 123.7
(2C), 111.8 (2C), 104.3 (2C), 83.8 (2C), 82.1 (2C), 82.0 (2C), 81.2
(2C), 74.6 (2C), 67.4 (2C), 26.8 (2C), 26.3 (2C); IR (CHCl3) ν =
1076, 1021; HRMS (ES): calcd for C32H38O10 [M]+: 582.2465; found:
582.2489.
Cyclophane (+)-E-18. From 20 mg (0.033 mmol) of dienyl
bis(dihydrofuran) (−)-12a, and after chromatography of the residue
using dichloromethane/ethyl acetate (4:1) as eluent, compound
(+)-E-18 (19 mg, 98%) as a pale brown solid was obtained; mp
299−300 °C; [α]D = +73.1 (c = 0.6 in CHCl3); 1H NMR (300 MHz,
CDCl3, 25 °C) δ: 7.32 (s, 4H), 6.05 (t, 2H, J = 1.4 Hz), 5.00 (dd, 2H,
J = 13.5, 1.6 Hz), 4.78 (dd, 2H, J = 13.5, 1.4 Hz), 4.38 (m, 2H), 4.30
(m, 2H), 4.18 (m, 2H), 4.15 (dd, 2H, J = 8.5, 6.7 Hz), 3.56 (dd, 2H, J
= 8.6, 5.1 Hz), 3.45 (m, 2H), 3.34 (d, 2H, J = 8.6 Hz), 1.34 (s, 6H),
1.30 (s, 6H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 168.4 (2C), 138.0
(2C), 132.2 (2C), 129.2 (4C), 126.0 (2C), 125.5 (2C), 109.8 (2C),
101.0 (2C), 77.2 (2C), 77.1 (2C), 66.5 (2C), 63.9 (2C), 41.4 (2C),
26.8 (2C), 24.9 (2C); IR (CHCl3) ν = 1743, 1208; HRMS (ES): calcd
for C32H36N2O8 [M]+: 576.2472; found: 576.2448.
NMR (300 MHz, CDCl3, 25 °C) δ: 7.16 (m, 10H), 6.95 (s, 4H), 5.73
(ddt, 2H, J = 17.0, 10.4, 6.6 Hz), 5.42 (d, 2H, J = 2.6 Hz), 5.10 (m,
4H), 4.77 (m, 6H), 4.33 (d, 2H, J = 5.1 Hz), 4.03 (d, 2H, J = 15.3 Hz),
3.65 (dd, 2H, J = 5.1, 2.6 Hz), 3.49 (s, 6H), 2.86 (d, 4H, J = 6.6 Hz);
13C NMR (75 MHz, CDCl3, 25 °C) δ: 168.5 (2C), 135.9 (2C), 135.2
(2C), 133.8 (2C), 132.8 (2C), 132.2 (2C), 128.5 (4C), 128.1 (4C),
127.7 (4C), 127.4 (2C), 117.2 (2C), 85.3 (2C), 83.3 (2C), 78.6 (2C),
59.6 (2C), 58.0 (2C), 44.7 (2C), 30.5 (2C); IR (CHCl3) ν = 1744,
1217; HRMS (ES): calcd for C42H45N2O6 [M + H]+: 673.3278;
found: 673.3251.
General Procedure for the Ruthenium-Catalyzed RCM
Reaction of Dienyl Bis(dihydrofurans) 11−14. Preparation of
Cyclophanes 16−20. The appropriate catalyst Ru-I, Ru-II, or Ru-
III, (0.01 mmol) was added in portions under argon to a solution
protected from the sunlight of the corresponding dienic compound
(0.10 mmol) in anhydrous dichloromethane (200 mL), and the
mixture was heated at reflux. The reaction was monitored by TLC.
After completion, the mixture was concentrated under reduced
pressure and was purified by column chromatography eluting with
ethyl acetate/hexanes or acetate/dichloromethane mixtures to give
analytically pure macrocyclic compounds 16−20. Spectroscopic and
analytical data for some representative pure forms of the above
cyclophanes follow.
Cyclophane 16a. From 50 mg (0.104 mmol) of dienyl
bis(dihydrofuran) 11a, and after chromatography of the residue
using hexanes/ethyl acetate (5:1) as eluent, compound 16a (47 mg,
1
quantiative yield) as a yellow oil was obtained; H NMR (300 MHz,
CDCl3, 25 °C) δ: 7.37 (m, 2H), 7.35 (s, 4H), 7.26 (s, 4H), 7.25 (m,
2H), 7.19 (ddd, 2H, J = 8.3, 7.3, 1.8 Hz), 7.06 (ddd, 2H, J = 8.5, 7.4,
1.8 Hz), 6.94 (td, 2H, J = 7.4, 0.7 Hz), 6.83 (td, 2H, J = 7.4, 0.8 Hz),
6.79 (dd, 2H, J = 8.4, 0.8 Hz), 6.66 (m, 2H), 6.66 (d, 2H, J = 7.8 Hz),
6.58 (ddd, 2H, J = 5.6, 3.3, 2.0 Hz), 6.25 (m, 2H, J = 1.9 Hz), 6.22 (q,
2H, J = 1.9 Hz), 5.97 (m, 2H), 5.85 (m, 2H), 5.10 (m, 2H), 4.92 (m,
2H), 4.76 (m, 4H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 154.0
(2C), 154.0 (2C), 143.7 (2C), 143.0 (2C) 132.4 (2C), 132.2 (2C),
131.4 (2C), 130.8 (2C), 128.9 (2C), 128.7 (2C), 128.7 (2C), 128.6
(2C), 128.5 (2C), 128.2 (2C), 126.7 (4C), 126.6 (4C), 121.2 (2C),
121.1 (2C), 120.9 (4C), 111.2 (2C), 110.9 (2C), 81.0 (2C), 80.7
(2C), 76.3 (2C), 76.1 (2C), 67.2 (2C), 66.6 (2C); IR (CHCl3) ν =
1681, 1222, 759; HRMS (ES): calcd for C30H26O4 [M]+: 450.1831;
found: 450.1811.
Cyclophane syn-16b. From 30 mg (0.055 mmol) of dienyl
bis(dihydrofuran) anti-11b, and after chromatography of the residue
using hexanes/ethyl acetate (6:1) as eluent, compound syn-16b (18
mg, 63%) as a colorless solid was obtained; mp 219−221 °C; 1H NMR
(300 MHz, CDCl3, 25 °C) δ: 7.34 (s, 4H), 7.20 (d, 2H, J = 2.7 Hz),
7.02 (dd, 2H, J = 8.8, 2.7 Hz), 6.60 (m, 1H), 6.57 (d, 2H, J = 8.8 Hz),
6.23 (q, 2H, J = 1.9 Hz), 5.80 (m, 2H), 5.10 (ddd, 2H, J = 13.8, 5.9,
1.7 Hz), 4.94 (ddd, 2H, J = 13.8, 3.4, 2.0 Hz), 4.75 (m, 4H); 13C NMR
(75 MHz, CDCl3, 25 °C) δ: 152.6 (2C), 143.1 (2C), 132.6 (2C),
132.2 (2C), 128.7 (2C), 128.4 (2C), 127.9 (2C), 126.6 (4C), 125.8
(2C), 121.6 (2C), 112.0 (2C), 80.6 (2C), 76.4 (2C), 66.8 (2C); IR
(CHCl3) ν = 1274; HRMS (ES): calcd for C30H24O4Cl2 [M]+:
518.1073; found: 518.1052.
Cyclophane (+)-Z-19. From 20 mg (0.032 mmol) of dienyl
bis(dihydrofuran) (+)-12b, and after chromatography of the residue
using hexanes/ethyl acetate (3:1) as eluent, compound (+)-Z-19 (16
mg, 84%) as a colorless solid was obtained; mp 157−159 °C; [α]D
=
+27.2 (c = 0.6 in CHCl3); 1H NMR (300 MHz, CDCl3, 25 °C) δ: 7.38
(s, 4H), 6.27 (t, 2H, J = 1.6 Hz), 5.48 (t, 2H, J = 3.9 Hz), 4.96 (dd,
2H, J = 14.2, 1.7 Hz), 4.73 (dd, 2H, J = 14.2, 1.6 Hz), 4.41 (dt, 2H, J =
8.8, 6.2 Hz), 4.18 (dd, 2H, J = 8.5, 6.8 Hz), 3.82 (m, 2H), 3.76 (d, 2H,
J = 8.8 Hz), 3.54 (dd, 2H, J = 8.5, 5.9 Hz), 3.24 (m, 2H), 2.08 (m,
4H), 1.43 (s, 6H), 1.35 (s, 6H); 13C NMR (75 MHz, CDCl3, 25 °C)
δ: 168.4 (2C), 136.6 (2C), 131.8 (2C), 129.2 (2C), 127.5 (4C), 127.2
(2C), 109.9 (2C), 99.7 (2C), 77.2 (2C), 76.2 (2C), 66.5 (2C), 65.9
J
dx.doi.org/10.1021/jo500993x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(2C), 40.3 (2C), 26.8 (2C), 26.6 (2C), 25.0 (2C); IR (CHCl3) ν =
1757, 1081; HRMS (ES): calcd for C34H40N2O8 [M]+: 604.2785;
found: 604.2812.
Procedure for the Ruthenium-Catalyzed Isomerization
Reaction of Dienyl Bis(dihydrofuran) (+)-15. Preparation of
Isomerized Open-Chain Adduct (+)-22. The appropriate catalyst
Ru-II or Ru-III (0.01 mmol) was added in portions under argon to a
solution protected from the sunlight of the dienic compound (+)-15
(40 mg, 0.06 mmol) in anhydrous dichloromethane (120 mL), and the
mixture was heated at reflux for 24 h. The mixture was concentrated
under reduced pressure and was purified by column chromatography
eluting with ethyl acetate/hexanes (1:3) to give 23 mg (56%) of
analytically pure 1,3-diene (+)-22.
Cyclophane (−)-E-19. From 40 mg (0.063 mmol) of dienyl
bis(dihydrofuran) (+)-12b, and after chromatography of the residue
using hexanes/ethyl acetate (3:1) as eluent, 38 mg (quantitative yield)
of compound (−)-E-19 (3:1 E/Z mixture) as a colorless solid were
1
obtained; mp 222−224 °C; [α]D = −55.4 (c = 1.0 in CHCl3); H
NMR (700 MHz, CDCl3, 25 °C) δ: 7.39 (s, 3H), 7.37 (s, 1H), 6.26 (s,
0.5H), 6.09 (s, 1.5H), 5.47 (t, 0.5H, J = 3.8 Hz), 4.96 (d, 1.5H, J =
13.8 Hz), 4.93 (d, 0.5H, J = 14.1 Hz), 4.74 (m, 1.5H), 4.73 (m, 0.5H),
4.72 (d, 1.5H, J = 13.8 Hz), 4.39 (dt, 0.5H, J = 8.5, 6.4 Hz), 4.32 (dt,
1.5H, J = 8.7, 6.4 Hz), 4.16 (m, 0.5H), 4.16 (dd, 1.5H, J = 15.9, 8.8
Hz), 3.80 (m, 1H), 3.78 (m, 1.5H), 3.53 (d, 1.5H, J = 8.7 Hz), 3.52
(m, 0.5H), 3.52 (m, 1.5H), 3.23 (m, 0.5H), 3.08 (t, 1.5H, J = 11.9 Hz),
2.15 (m, 1H), 1.95 (m, 3H), 1.41 (s, 1.5H), 1.34 (s, 1.5H), 1.31 (s,
4.5H), 1.30 (s, 4.5H); 13C NMR (175 MHz, CDCl3, 25 °C) δ: 168.5
(2C-m), 168.0 (2C-M), 137.8 (2C-M), 136.5 (2C-m), 132.7 (2C-M),
131.7 (2C-m), 130.0 (2C-M), 129.2 (2C-m), 128.6 (4C-M), 127.4
(4C-m), 127.3 (2C-M), 127.2 (2C-m), 109.9 (2C-m), 109.8 (2C-M),
100.4 (2C-M), 99.7 (2C-m), 77.5 (2C-M), 77.3 (2C-m), 76.7 (2C-M),
76.2 (2C-m), 67.1 (2C-M), 66.4 (2C-M), 66.4 (2C-m), 65.8 (2C-m),
40.4 (2C-M), 40.3 (2C-m), 33.7 (2C-M), 26.7 (2C-m), 26.7 (2C-M),
26.6 (2C-m), 25.1 (2C-M), 25.0 (2C-m); IR (CHCl3) ν = 1747, 1079;
HRMS (ES): calcd for C34H40N2O8 [M]+: 604.2785; found: 604.2812.
Cyclophane (+)-Z-20a. From 30 mg (0.04 mmol) of dienyl
bis(dihydrofuran) (+)-14a, and after chromatography of the residue
using hexanes/ethyl acetate (3:1) as eluent, compound (+)-Z-20a (22
mg, 71%) as a pale brown oil was obtained; [α]D = +37.8 (c = 1.1 in
Isomerized Open-Chain Adduct (+)-22. Colorless oil; [α]D
=
+7.7 (c = 0.5 in CHCl3); 1H NMR (300 MHz, CDCl3, 25 °C) δ: 7.11
(m, 12H), 6.19 (d, 1H, J = 16.3 Hz), 5.68 (m, 1H, J = 17.0, 10.4, 6.6
Hz), 5.63 (dq, 1H, J = 15.7, 6.9 Hz), 5.43 (brs, 2H), 5.11 (m, 2H),
4.76 (m, 6H), 4.35 (m, 2H), 4.03 (m, 2H), 3.66 (m, 2H), 3.48 (s, 3H),
3.49 (s, 3H), 2.86 (m, 2H), 1.84 (d, 3H, J = 6.6 Hz); 13C NMR (75
MHz, CDCl3, 25 °C) δ: 168.4 (2C), 136.1 (2C), 135.3, 135.3, 133.8,
132.9 (2C), 132.3, 132.2, 131.4, 128.5 (4C), 128.1 (4C), 127.7 (4C),
127.4 (2C), 122.1, 117.1, 85.4, 85.2, 83.4 (2C), 78.6 (2C), 59.6, 59.6,
58.0 (2C), 44.7, 30.5 (2C), 18.9; IR (CHCl3) ν = 1738, 1213; HRMS
(ES): calcd for C42H45N2O6 [M + H]+: 673.3278; found: 673.3249.
ASSOCIATED CONTENT
■
S
* Supporting Information
ORTEP drawing of compounds anti-4 and E-19 as well as
1
copies of the H NMR and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
CHCl3); H NMR (300 MHz, CDCl3, 25 °C) δ: 7.63 (d, 4H, J = 9.0
AUTHOR INFORMATION
Corresponding Authors
*E-mail: alcaideb@quim.ucm.es.
*E-mail: Palmendros@iqog.csic.es.
Hz), 7.40 (s, 4H), 6.93 (d, 4H, J = 9.0 Hz), 5.14 (t, 2H, J = 7.4 Hz),
5.01 (d, 2H, J = 13.3 Hz), 4.80 (d, 2H, J = 13.3 Hz), 4.56 (dt, 2H, J =
8.5, 6.7 Hz), 4.37 (dd, 2H, J = 8.5, 7.5 Hz), 3.90 (s, 6H), 3.81 (d, 2H, J
= 8.6 Hz), 3.66 (dd, 2H, J = 8.5, 6.4 Hz), 2.94 (d, 4H, J = 7.3 Hz), 1.78
(s, 6H), 1.70 (s, 6H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 166.3
(2C), 156.6 (2C), 140.3 (2C), 134.6 (2C), 131.4 (2C), 130.5 (2C),
129.2 (4C), 119.9 (4C), 119.2 (2C), 113.9 (4C), 109.7 (2C), 101.1
(2C), 78.6 (2C), 77.2 (2C), 67.0 (2C), 66.4 (2C), 55.3 (2C), 26.4
(2C), 25.6 (2C), 24.6 (2C); IR (CHCl3) ν = 1753, 1222; HRMS
(ES): calcd for C46H48N2O10 [M]+: 788.3309; found: 788.3304.
Reaction of Dienyl Bis(dihydrofuran) (+)-14b. From 52 mg
(0.07 mmol) of dienyl bis(dihydrofuran) (+)-14b, and after
chromatography of the residue using hexanes/ethyl acetate (4:1) as
eluent, 11 mg (22%) of the less polar compound (+)-Z-20b and 10 mg
(19%) of the more polar compound (+)-21b were obtained.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this work by MINECO (Projects CTQ2012-33664-
C02-01 and CTQ2012-33664-C02-02) is gratefully acknowl-
edged. M.T.Q. thanks MEC for a predoctoral grant. C.L. thanks
MEC for a studentship (“beca de colaboracion
́
”).
REFERENCES
■
Cyclophane (+)-Z-20b. Colorless oil; [α]D = +45.2 (c = 1.1 in
1
(1) (a) Progress in Allene Chemistry; Alcaide, B.; Almendros, P., Eds.;
Chem. Soc. Rev. 2014, 43, 2879−3205 (issue 9, themed collections);.
(b) Lechel, T.; Pfrengle, F.; Reissig, H.-U.; Zimmer, R. ChemCatChem
2013, 5, 2100. (c) Yu, S.; Ma, S. Angew. Chem., Int. Ed. 2012, 51, 3074.
(d) Rivera-Fuentes, P.; Diederich, F. Angew. Chem., Int. Ed. 2012, 51,
2818. (e) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994.
(f) Alcaide, B.; Almendros, P. Chem. Rec. 2011, 11, 311. (g) Aubert,
C.; Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A. Chem. Rev.
2011, 111, 1954. (h) Brasholz, M.; Reissig, H.-U.; Zimmer, R. Acc.
Chem. Res. 2009, 42, 45. (i) Cumulenes and Allenes. Science of
Synthesis, Houben-Weyl Method of Molecular Transformation; Krause,
N., Ed.; George Tieme: Sttutgart, 2007; Vol. 44. (j) Ma, S. Chem. Rev.
2005, 105, 2829. (k) Modern Allene Chemistry, Krause, N., Hashmi, A.
S. K., Eds.; Wiley-VCH: Weinheim, 2004. (l) Hashmi, A. S. K. Angew.
Chem., Int. Ed. 2000, 39, 3590.
CHCl3); H NMR (300 MHz, CDCl3, 25 °C) δ: 7.07 (m, 5H), 6.98
(s, 4H), 5.02 (t, 2H, J = 7.1 Hz), 4.88 (d, 2H, J = 13.1 Hz), 4.77 (d,
2H, J = 14.5 Hz), 4.65 (d, 2H, J = 13.2 Hz), 4.18 (m, 4H), 4.44 (m,
2H), 3.48 (dd, 2H, J = 8.2, 6.1 Hz), 3.25 (d, 2H, J = 8.9 Hz), 2.80 (d,
4H, J = 6.3 Hz), 1.69 (s, 6H), 1.51 (s, 6H); 13C NMR (75 MHz,
CDCl3, 25 °C) δ: 168.5 (2C), 140.1 (2C), 135.1 (2C), 131.0 (2C),
129.4 (2C), 129.0 (4C), 128.7 (4C), 128.2 (4C), 127.4 (2C), 119.4
(2C), 109.6 (2C), 101.7 (2C), 78.4 (2C), 77.2 (2C), 66.3 (2C), 64.6
(2C), 45.2 (2C), 31.5 (2C), 26.4 (2C), 24.6 (2C); IR (CHCl3) ν =
1759, 1210; HRMS (ES): calcd for C46H48N2O8 [M]+: 756.3411;
found: 756.3408.
Isomerized Open-Chain Adduct (+)-21b. Colorless oil; [α]D
=
+53.1 (c = 1.1 in CHCl3); 1H NMR (300 MHz, CDCl3, 25 °C) δ: 7.07
(m, 10H), 7.00 (s, 4H), 6.04 (d, 1H, J = 16.1 Hz), 5.75 (m, 1H), 5.69
(dq, 1H, J = 16.0, 6.7 Hz), 5.09 (m, 4H), 4.80 (m, 6H, J = 13.3 Hz),
4.45 (m, 2H), 4.18 (m, 4H), 3.47 (m, 2H), 3.25 (d, 1H, J = 8.8 Hz),
3.23 (d, 1H, J = 9.0 Hz), 2.84 (m, 2H), 1.80 (d, 3H, J = 6.6 Hz), 1.34
(s, 12H); 13C NMR (75 MHz, CDCl3, 25 °C) δ: 168.3, 168.2, 138.1,
138.0, 135.0, 134.8, 134.0 (2C), 131.9, 131.1, 130.9, 129.9, 129.7,
129.3 (2C), 129.2 (2C), 128.8 (2C), 128.8 (2C), 128.2 (2C), 128.2
(2C), 127.6, 127.5, 122.3, 117.0, 109.6 (2C), 101.6, 101.6, 78.2 (2C),
70.2 (2C), 66.4, 66.3, 64.6, 64.5, 45.2 (2C), 30.3, 26.4 (2C), 24.5
(2C), 18.8; IR (CHCl3) ν = 1760, 1210; HRMS (ES): calcd for
C48H52N2O8 [M]+: 784.3724; found: 784.3761.
(2) (a) Poonoth, M.; Krause, N. Adv. Synth. Catal. 2009, 351, 117.
(b) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem.Eur. J. 2009,
15, 9987. (c) Deng, Y.; Shi, Y.; Ma, S. Org. Lett. 2009, 11, 1205.
(3) For selected reviews, see: (a) Wisniewska, H. M.; Jarvo, E. R. J.
Org. Chem. 2013, 78, 11629. (b) Marshall, J. A. Chem. Rev. 2000, 100,
316. (c) Yamamoto, H. In Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.3.
(d) Panek, J. S. In Comprehensive Organic Synthesis; Schreiber, S. L.,
Ed.; Pergamon Press: Oxford, 1991;, Vol. 1, p 595.
K
dx.doi.org/10.1021/jo500993x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(4) (a) Guo, L.-N.; Gao, H.; Mayer, P.; Knochel, P. Chem.Eur. J.
2010, 16, 9829. (b) Fu, F.; Hoang, K. L. M.; Loh, T.-P. Org. Lett. 2008,
10, 3437. (c) Miao, W.; Chung, L. W.; Wu, Y.-D.; Chan, T. H. J. Am.
Chem. Soc. 2004, 126, 13326.
Rep. 2005, 22, 162. (d) Wessjohann, L. A.; Ruijter, E.; García-Rivera,
D.; Brandt, W. Mol. Diversity 2005, 9, 171.
(16) (a) Modern Cyclophane Chemistry; Gleiter, R., Hopf, H., Eds.;
Wiley-VCH: Weinheim, 2004. (b) Cyclophane Chemistry; Vogtle, F.,
Ed.; John Wiley & Sons: Chichester, U.K., 1999.
(5) For selected examples of the allenylation reaction, see:
(17) (a) Tatsuta, K. J. Antibiot. 2013, 66, 107. (b) Xavier, N. M.;
Rauter, A. P. Pure Appl. Chem. 2012, 84, 803. (c) Driggers, E. M.;
Hale, S. P.; Lee, J. J.; Terrett, N. K. Nat. Rev. Drug Discovery 2008, 7,
608. (d) Andre, S.; Sansone, F.; Kaltner, H.; Casnati, A.; Kopitz, J.;
́
Gabius, H.-J.; Ungaro, R. ChemBioChem. 2008, 9, 1649. (e) Metaferia,
B. B.; Chen, L.; Baker, H. L.; Huang, X.-Y.; Bewley, C. A. J. Am. Chem.
(a) Munoz-Bascon
́
, J.; Hernan
Alvarez-Corral, M.; Rosales, A.; Rodríguez-García, I.; Oltra, J. E.
, J.; Sancho-Sanz, I.;
́
dez-Cervantes, C.; Padial, N. M.;
̃
́
Chem.Eur. J. 2014, 20, 801. (b) Munoz-Bascon
́
̃
́
Alvarez-Manzaneda, E.; Rosales, A.; Oltra, J. E. Chem.Eur. J. 2012,
18, 14479. (c) Park, J.; Kim, S. H.; Lee, P. H. Org. Lett. 2008, 10, 5067.
(d) Park, C.; Lee, P. H. Org. Lett. 2008, 10, 3359. (e) Inoue, M.;
Nakada, M. Angew. Chem., Int. Ed. 2006, 45, 252. (f) Lin, M.-J.; Loh,
T.-P. J. Am. Chem. Soc. 2003, 125, 13042. (g) Alcaide, B.; Almendros,
P.; Aragoncillo, C. Org. Lett. 2000, 2, 1411.
Soc. 2007, 129, 2434. (f) Furstner, A. Eur. J. Org. Chem. 2004, 943.
̈
(g) Myles, D. C. Curr. Opin. Biotechnol. 2003, 14, 627. (h) Alvarez-
̈
Elcoro, S.; Yao, J. D. C. Macrolide Antibiotics; Omura, S., Ed.; Elsevier,
New York, 2002; Chapter 7, pp 363−4025.
(18) For their antibacterial, antiviral, antitumoral, antifungal, and
(6) For the two-step preparation of 1,ω-bisallenols promoted by tin,
see ref 2c. For the synthesis of allene−alkyne hybrids on the indium-
mediated reaction between 1,6-dibromo-2,4-hexadiyne and carbonyls,
see: Kim, S.; Lee, K.; Seomoon, D.; Lee, P. H. Adv. Synth. Catal. 2007,
349, 2449.
(7) For selected reviews on organic reactions in aqueous media, see:
(a) Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302.
(b) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725. (c) Organic
anti-inflammatory properties, see: (a) Satge,
B.; Champavier, Y.; Krausz, P. Carbohydr. Res. 2004, 1243. (b) Ortiz-
Mellet, C.; Defaye, J.; García Fernan
́
C.; Granet, R.; Verneuil,
́
dez, J. M. Chem.Eur. J. 2002, 8,
1983. (c) Szejtli, J. Chem. Rev. 1998, 98, 1743. (d) Nepogodiev, S. A.;
Stoddart, J. F. Chem. Rev. 1998, 98, 1959. (e) Aoyama, Y.; Matsuda, Y.;
Chuleeraruk, J.; Nishiyama, K.; Fujimoto, K.; Fujimoto, T.; Shimizu,
T.; Hayashida, O. Pure Appl. Chem. 1998, 70, 2379. (f) Fujimoto, T.;
Shimizu, C.; Hayashida, O.; Aoyama, Y. J. Am. Chem. Soc. 1997, 119,
6676.
Reactions in Water: Principles, Strategies and Applications; Linstrom, U.
̈
M., Ed.; Blackwell: Oxford, 2007. (d) Li, C. J.; Chen, L. Chem. Soc. Rev.
2006, 35, 68. (e) Pirrung, M. C. Chem.Eur. J. 2006, 12, 1312. (f) Li,
(19) The β-lactam nucleus is the key structural motif in biologically
relevant compounds such as antibiotics, enzyme inhibitors, neuro-
therapeutics, antitumorals, and gene activators. For selected references,
see: (a) Chemistry and Biology of β-Lactam Antibiotics; Morin, R. B.,
Gorman, M., Eds.; Academic: New York, NY, 1982; Vols. 1−3.
(b) Southgate, R.; Branch, C.; Coulton, S.; Hunt, E. In Recent Progress
in the Chemical Synthesis of Antibiotics and Related Microbial Products;
Lukacs, G., Ed.; Springer: Berlin, 1993; Vol. 2, p 621. (c) Veinberg, G.;
Vorona, M.; Shestakova, M.; Kanepe, I.; Lukevics, E. Curr. Med. Chem.
2003, 10, 1741. (d) Banik, B. K.; Banik, I.; Becker, F. F. In Topics in
Heterocyclic Chemistry; Gupta, R. R., Banik, B. K., Eds.; Springer:
Berlin-Heidelberg, 2010; pp 394−373. (e) Rothstein, J. D.; Patel, S.;
Regan, M. R.; Haenggeli, C.; Huang, Y. H.; Bergles, D. E.; Jin, L.;
Hoberg, M. D.; Vidensky, S.; Chung, D. S.; Toan, S. V.; Bruijin, J. I.;
Su, Z.-z.; Gupta, P.; Fisher, P. B. Nature 2005, 433, 73.
(20) (a) Kamath, A.; Ojima, I. Tetrahedron 2012, 68, 10640.
(b) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107,
4437. (c) Alcaide, B.; Almendros, P. Curr. Med. Chem. 2004, 11, 1921.
(d) Deshmukh, A. R. A. S.; Bhawal, B. M.; Krishnaswamy, D.;
Govande, V. V.; Shinkre, B. A.; Jayanthi, A. Curr. Med. Chem. 2004, 11,
1889.
(21) (a) Ibrahim, Y. A.; Al-Azemi, T. F.; Abd El-Halim, M. D. J. Org.
Chem. 2010, 75, 4508. (b) Sliwa, A.; Dive, G.; Jiwan, J.-L. H.;
Marchand-Brynaert, J. Tetrahedron 2010, 66, 9519. (c) Sliwa, A.; Dive,
G.; Marchand-Brynaert, J. Chem.Asian J. 2012, 7, 425. (d) Ibrahim,
Y. A.; Al-Awadi, N. A.; Al-Azemi, T. F.; Abraham, S.; John, E. RSC Adv.
2013, 3, 6408.
C. J. Chem. Rev. 2005, 105, 3095. (g) Lindstrom, U. M. Chem. Rev.
̈
2002, 102, 2751. (h) Manabe, K.; Kobayashi, S. Chem.Eur. J. 2002,
8, 4095. (i) Ribe, S.; Wipf, P. Chem. Commun. 2001, 299. (j) Li, C. J.;
Chan, T. H. Tetrahedron 1999, 55, 11149. (k) Paquette, L. A. In Green
Chemistry: Frontiers in Benign Chemical Synthesis and Processing;
Anastas, P. T., Williamson, T. C., Eds.; Oxford University Press:
New York, 1998.
(8) (a) Lu, W.; Chan, T. H. J. Org. Chem. 2001, 66, 3467. (b) Yadav,
J. S.; Bandyopadhyay, A.; Reddy, B. V. S. Tetrahedron Lett. 2001, 42,
6385. (c) Kumar, H. M. S.; Anjaneyulu, E.; Reddy, E. J.; Yadav, J. S.
Tetrahedron Lett. 2000, 41, 9311. (d) Li, C. J.; Chan, T. H. Tetrahedron
1999, 55, 11149.
(9) See, for instance: (a) Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett,
N. K. Nat. Rev. Drug Discovery 2008, 7, 608. (b) Parenty, A.; Moreau,
X.; Campagne, J. M. Chem. Rev. 2006, 106, 911. (c) Gradillas, A.;
́
Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086. (d) Butler, M.
S. Nat. Prod. Rep. 2005, 22, 162. (e) Wessjohann, L. A.; Ruijter, E.;
Garcia-Rivera, D.; Brandt, W. Mol. Diversity 2005, 9, 171.
(10) (a) Furstner, A. Chem. Commun. 2011, 47, 6505. (b) Samo-
̈
jłowicz, C.; Bieniek, M.; Grela, K. Chem. Rev. 2009, 109, 3708. (c) van
Otterlo, W. A. L.; de Koning, C. B. Chem. Rev. 2009, 109, 3743.
(d) Monfette, S.; Fogg, D. E. Chem. Rev. 2009, 109, 3783. (e) Zhang,
W.; Moore, J. S. Adv. Synth. Catal. 2007, 349, 93.
(11) For a paper on furan-based cyclophanes, which also is based on
the principle of bidirectional synthesis but with a desymmetrizing final
step, see: Hashmi, A. S. K.; Schwarz, L.; Bolte, M. Eur. J. Org. Chem.
2004, 1923.
(12) For the beneficial use of NH4Cl in the monoallenylation
reaction, see: (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem.
Eur. J. 2002, 8, 1719. For the beneficial use of NH4Cl in the allylation
reaction, see: (b) Chappell, M. D.; Halcomb, R. L. Org. Lett. 2000, 2,
2003.
(13) CCDC-953186 contains the supplementary crystallographic
data for compound 4 in this paper (www.ccdc.cam.ac.uk/data_
request/cif).
(14) For the first AuCl3-catalyzed reaction of allenes, see: (a) Hashmi,
A. S. K.; Schwarz, L.; Choi, J. H.; Frost, T. M. Angew. Chem., Int. Ed.
2000, 39, 2285. Au(III) might be reduced to Au(I) in the presence of
allenylcarbinols: (b) Hashmi, A. S. K.; Blanco, M. C.; Fischer, D.; Bats,
J. W. Eur. J. Org. Chem. 2006, 1387.
(22) (a) Quigley, B. L.; Grubbs, R. H. Chem. Sci. 2014, 5, 501.
(b) Gottumukkala, A. L.; Madduri, A. V. R.; Minnaard, A. J.
ChemCatChem 2012, 4, 462.
(23) CCDC 943246 contains the supplementary crystallographic
data for compound E-19 in this paper (www.ccdc.cam.ac.uk/data_
request/cif).
(24) For nonmetathetic behavior patterns of Grubb’s carbenes, see:
(a) Alcaide, B.; Almendros, P.; Luna, A. Chem. Rev. 2009, 109, 3817.
(b) Alcaide, B.; Almendros, P.; Alonso, J. M. Chem.Eur. J. 2006, 12,
2874. (c) Alcaide, B.; Almendros, P. Chem.Eur. J. 2003, 9, 1258.
(15) (a) Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett, N. K. Nat. Rev.
Drug Discovery 2008, 7, 608. (b) Driggers, E. M.; Hale, S. P.; Lee, J.;
Terrett, N. K. Nature Reviews 2008, 7, 608. (c) Butler, M. S. Nat. Prod.
L
dx.doi.org/10.1021/jo500993x | J. Org. Chem. XXXX, XXX, XXX−XXX