Cobalt- versus ruthenium-catalyzed Alder-ene reaction for the synthesis of credneramide A and B

Article abstract of DOI:10.1021/jo3007896

The first synthesis of the natural products credneramide A and B was accomplished by utilizing Alder-ene reactions between a terminal alkene and an internal alkyne to generate the rather uncommon 1,4-diene substructure of these compounds. Moreover, two different short linear sequences toward these targets are evaluated using either a cobalt-catalyzed Alder-ene reaction of 1-chloropent-1-yne or a ruthenium-catalyzed Alder-ene reaction of 1-trimethylsilyl-1-pentyne with 5-hexenoic acid derivatives in the key step transformation. In addition, saponification of the primary Alder-ene product derived from the cobalt-catalyzed Alder-ene reaction led to credneric acid, the biological precursor of both natural products.

Full text of DOI:10.1021/jo3007896

Note
pubs.acs.org/joc
Cobalt- versus Ruthenium-Catalyzed Alder−Ene Reaction for the
Synthesis of Credneramide A and B
Florian Erver and Gerhard Hilt*
Fachbereich Chemie, Philipps-Universitat Marburg, Hans-Meerwein-Strasse 35043 Marburg, Germany
̈
S
* Supporting Information
ABSTRACT: The first synthesis of the natural products
credneramide A and B was accomplished by utilizing Alder−
ene reactions between a terminal alkene and an internal alkyne
to generate the rather uncommon 1,4-diene substructure of
these compounds. Moreover, two different short linear
sequences toward these targets are evaluated using either a
cobalt-catalyzed Alder−ene reaction of 1-chloropent-1-yne or a
ruthenium-catalyzed Alder−ene reaction of 1-trimethylsilyl-1-
pentyne with 5-hexenoic acid derivatives in the key step transformation. In addition, saponification of the primary Alder−ene
product derived from the cobalt-catalyzed Alder−ene reaction led to credneric acid, the biological precursor of both natural
products.
he ultimate benchmark for every established synthetic
The recent discovery of credneramide A (1) and B (2)
Tmethod is application in natural product synthesis, in prompted us to address their synthesis utilizing a cobalt-
catalyzed Alder−ene reaction as the key step of the formation
of the carbon backbone of these natural products.6 The
compounds were isolated from the organic extract of the
cyanobacterium cf. Trichodesmium sp. nov. which was collected
near the Credner Islands, Papua New Guinea, from which the
compounds’ names originate. It was found that both
compounds are biologically active, especially in the inhibition
of calcium oscillation in cerebrocortical mouse neurons at low
micromolar concentrations (1, IC50 4.0 μM; 2, IC50 3.8 μM).
From a synthetic point of view, the scaffold of both
substances should be concisely accessible by amidation of a
suitable 5-hexenoic acid derivative and a transition-metal-
catalyzed Alder−ene reaction with a 1-pentyne-derived
component as is outlined in Scheme 2.
advanced materials science, and in industrial processes. As
shown in the past decade, cobalt-catalyzed transformations1 are
a powerful tool for the atom-economic and stereoselective
construction of cyclic2 and acyclic3 organic building blocks. The
immediate product of cobalt-catalyzed carbon−carbon bond
formation reactions between unsaturated starting materials such
as alkenes, alkynes, or 1,3-dienes exhibits cyclic as well as
acyclic 1,4-diene substructures (Scheme 1).
Scheme 1
Scheme 2
As a consequence, we are particularly interested in natural
products and materials bearing the rather infrequent acyclic 1,4-
diene motif which by retrosynthetic analysis can be constructed
via a cobalt-catalyzed 1,4-hydrovinylation or an Alder−ene
reaction. In fact, we have already applied the 1,4-hydro-
vinylation successfully in the short synthesis of moenocinol, the
aglycon of the antibiotic moenomycin A.4 On the other hand,
we realized a short racemic synthesis of hepialone as well as of a
lipid isolated from vanilla beans via ozonolysis of branched 1,4-
dienes generated by cobalt-catalyzed 1,4-hydrovinylation
reactions of allyl pinacolboronic ester.5
At first, we began our investigation concerning the synthesis
of the credneramides utilizing the well-established ruthenium-
catalyzed Alder−ene reaction described by Trost.7 However, in
a simple test reaction, we immediately recognized that the
Received: April 20, 2012
Published: May 8, 2012
© 2012 American Chemical Society
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Note
Scheme 3
ruthenium-catalyzed Alder−ene reaction of a 1-chloro-1-
pentyne (3)8 with 1-hexene provided predominantly the
wrong linear regioisomer 4 concerning the carbon−carbon
bond formation at the alkyne subunit, while the desired E-
double bond configuration could be formed via the ruthenium-
induced double bond migration in the alkene component
(Scheme 3).
with the respected amines 7a/7b.12 Furthermore, credneric acid
(8), the natural product and the biological precursor of
credneramide A and B, could be obtained by simple
saponification (Scheme 4).13
Scheme 4
Therefore, we investigated the alternative route involving a
cobalt-catalyzed Alder−ene reaction9 by reacting 1-chloro-1-
pentyne (3) with methyl 5-hexenoate (5) for the formation of
the desired branched regioisomer found in the natural
products.10 As free carboxylic acids and amides are not
tolerated by the cobalt catalyst, 5-hexenoic acid was introduced
as its methyl ester. Unfortunately, the reaction proceeded
sluggishly in dichloromethane with poor conversion of the
alkene component 5 and the major product in these reactions
was trichlorotripropylbenzene, which was formed in a cyclo-
trimerization reaction of the alkyne.11 We observed that
increasing the amount of the chloroalkyne or the catalyst
loading did not lead to complete conversion of the alkene
component but produced even more cyclotrimerization by-
product. These inhibited the Alder−ene reaction by catalyst
deactivation. As known from our initial studies,9 the use of
acetone as a solvent led to the best chemoselectivity in the
cobalt-catalyzed Alder−ene reaction, associated by diminished
reactivity. Nevertheless, the reaction conditions could be
optimized by using acetone as solvent of choice and also by
portioning the catalyst and alkyne loadings over 2 days. With
these modified conditions and applying a higher catalyst
loading, we were able to obtain the desired methyl ester of
credneric acid (6) with high regio- and stereocontrol in a good
yield of 80%, accompanied by small amounts of unreacted
methyl 5-hexenoate which could not be separated from the
desired product completely.
To date, we attribute the different regioselectivities of the
ruthenium versus the cobalt catalyst in the Alder−ene reaction
to the electronic nature of these metal fragments; assigning a
more nucleophilic character to the CpRu+ and a more
electrophilic reactivity to the Co(dppp)+ fragment, while steric
factors are not believed to be of high relevance for the observed
regioselectivities. These electronically based assumptions could
explain the formation of different regioisomers of the
metallacyclic intermediates, but more detailed investigations
for the cobalt-catalyzed Alder−ene reaction are necessary to
obtain additional data and to establish the cobalt catalysis as a
complementary synthetic method.
Hence, both credneramide A and B as well as credneric acid
could be synthesized in two steps starting from methyl 5-
hexenoate in excellent overall yields of 50%, 53% and 77%.
In addition, we were also interested in comparing these
results obtained with the cobalt-catalyzed Alder−ene reaction
with a ruthenium-catalyzed route for the synthesis of
credneramide A and B. Therefore, we substituted the chloro-
substituted 1-pentyne (3) with the trimethylsilyl-substituted
alkyne 11 (Scheme 4).7 This alternative approach led us to
three commercially available building blocks: 1-trimethylsilyl-1-
pentyne (11), 5-hexenoic acid (9), and the two primary amines
7a and 7b, respectively. As ruthenium-catalyzed Alder−ene
reactions between carboxylic acid functionalized alkenes with 1-
trimethylsilyl-1-alkynes are not known, purification of carbox-
ylic acids are difficult and because of the rather expensive
ruthenium-based catalyst, we decided to perform first the
amidation between 5-hexenoic acid (9) with the respective
amine 7a/7b. Adopting an amidation procedure with very
similar substrates,14 we could obtain the respective 5-hexenoic
amides 10a/10b in good yields (Scheme 5).
Although the ruthenium-catalyzed Alder−ene reaction
tolerates all kinds of functional groups as acetals, alcohols,
ether, ester, carbonates, ketones, sulfonamides, and silyl
groups,7,10a we were not sure if the catalyst accepted simple
amides. Fortunately, the ruthenium-catalyzed Alder−ene
reaction between 1-trimethylsilyl-1-pentyne (11) and the
respective 5-hexenoic amides 10a and 10b proceeded smoothly
within 3 h at ambient temperature to give the corresponding
products 12a and 12b in good yields as single regio- and
With the key intermediate methyl credneroate (6) in hand,
the completion of the syntheses of credneramides A (1) and B
(2) was accomplished via AlMe3-mediated amidation reactions
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Note
Scheme 5
ammonium molybdate, 1.6 g of ceric ammonium molybdate, 80 mL of
concentrated sulfuric acid, and 720 mL of water) with subsequent
stereoisomers. Next, the credneramides 1 and 2 were accessible
via chlorodesilylation reaction, which is described to proceed
with retention of the double-bond configuration. However, the
use of the original protocol15 established by Paige et al. for the
synthesis of (S)-jamaicamide C carboxylic acid, a building block
of related natural products also isolated from a cyanobacterium,
led to the generation of various byproducts which were difficult
to separate from the products due to their very similar polarity.
We found, that the reaction proceeded best by lowering the
original reaction temperature from 50 to 30 °C to inhibit side-
reactions. Nonetheless, the desired products were always
accompanied by their minor Z-configurated vinyl chloride
isomers, which diminished the yields in the last step. Thus,
credneramide A (1) and B (2) could be obtained after three
linear steps starting from 5-hexenoic acid in good overall yields
of 28% and 31%, respectively.
In conclusion, we have demonstrated that the natural
products credneramides A and B can be accessed by a
transition-metal-catalyzed Alder−ene reaction, constructing the
rather challenging 1,4-diene subunit in a single step. The
ruthenium and the cobalt catalyst proved again to complement
each other, as the ruthenium-catalyst tolerated a 1-trimethyl-
silyl-substituted alkyne and a free amide as substrates in
contrast to the cobalt catalyst, which is unable to perform a
reaction between such components. On the other hand, the
cobalt catalyst produces, unlike its opponent, the desired
regioisomer in the Alder−ene reaction of a 1-chlorinated alkyne
with the corresponding terminal olefin. In comparison, the
ruthenium-route proved to be advantageous concerning the
availability of starting materials and the straightforward
synthesis, though the sequence suffers from the final
chlorodesilylation reaction. In contrast, the cobalt-catalyzed
route is disadvantaged by the commercial unavailability of the
chloroalkyne but displays its benefits by generating the 1,4-
dienyl chloride subunit efficiently and stereoselectively in a
single step.
1
heating by using a heat gun. H and 13C NMR spectra were obtained
using CDCl3 as a solvent and tetramethylsilane as internal standard.
Chemical shifts δ are reported in ppm downfield from tetramethylsi-
lane. Coupling constants are indicated in Hz with multiplicities
denoted as s (singlet), d (doublet), t (triplet), q (quartet), p (pentet),
sext (sextet), and m (multiplet). Broad singlets are reported as bs. IR
spectra were measured on an FT-IR spectrometer and are reported in
wave numbers (cm−1). High-resolution mass spectra were acquired
using electron impact ionization (EI) or atmospheric pressure
chemical ionization (APCI).
Preparation of 1-Chloro-pent-1-yne (3). Following a literature
procedure,8a a solution of triphenylphosphine (4.0 equiv) in
dichloromethane (0.625 M) was treated with butyraldehyde (1.0
equiv) and tetrachloromethane (2.0 equiv) and was stirred overnight
at room temperature. The solvent was then evaporated (40 °C, 400
mbar), and the residue was treated with pentane (1.0 mL/g residue).
The solid was filtered, and the filtrate was distilled to give 1,1-
dichloropent-1-ene in 43% yield as a clear and colorless liquid. The
compound was mixed with powdered potassium hydroxide (1.0 equiv)
and Aliquat 336 (6 mol−%). The reaction mixture was stirred for 2 h
at 90 °C. Then the product was distilled off directly and dried by
filtration through a short plug of a mixture of silica gel and magnesium
sulfate. The product was obtained as a clear and colorless liquid in 62%
yield.
1-Chloro-pent-1-yne (3): colorless liquid; 2.70 g (26.36 mmol,
1
62%); H NMR (300 MHz, CDCl3) δ 2.15 (t, J = 7.0 Hz, 2H), 1.53
(sext, J = 7.3 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 69.6, 57.1, 21.8, 20.7, 13.4; HRMS (EI, ICP, m/z) calcd for
C5H735Cl 102.0236, found 102.0236; IR (film, cm−1) 2965, 2936,
2875, 2241, 1618, 1459, 1381, 1336, 1273, 1225, 1087, 1007, 915, 848,
786, 745, 645, 603, 555, 476.
General Procedure A for the Ruthenium-Catalyzed Alder−
Ene Reaction. Following a literature procedure by Trost,7 the alkyne
(1.0 equiv), the alkene (1.0 equiv), and tris(acetonitrile)-
cyclopentadienylruthenium(II) hexafluorophosphate (10 mol %)
were dissolved in acetone (1 M) and stirred for 3 h at room
temperature. The reaction mixture was then filtered over a small plug
of silica gel. After evaporation of the solvent, the crude product was
purified by flash column chromatography (SiO2, eluent) to give the
Alder−ene products 4/12a/12b as clear oils.
EXPERIMENTAL SECTION
■
(4Z,7E)-5-Chloroundeca-4,7-diene (4): pale yellow oil; 124 mg
General Experimental Methods. All reactions were carried out
under an argon atmosphere in heat gun-dried glassware and were
stirred magnetically. Unless otherwise noted, all reactions were
performed with anhydrous solvents, and ZnI2 was dried in vacuo at
150 °C prior to use. Commercially available materials were used
without further purification. Flash chromatography was performed on
silica gel 60 (230−400 mesh), and analytical thin-layer chromatog-
raphy (TLC) was carried out on silica gel 60 F-254 precoated
aluminum plates. The TLC plates were analyzed by short-wave UV
illumination and by dipping in CAM stain (composed of 40 g of
1
(0.67 mmol, 67%); eluent pentane; H NMR (300 MHz, CDCl3) δ
5.58−5.37 (m, 3H), 2.98 (d, J = 6.2 Hz, 2H), 2.15 (q, J = 7.4 Hz, 2H),
2.01 (q, J = 6.8 Hz, 2H), 1.47−1.34 (m, 4H), 0.94−0.87 (m, 6H); 13C
NMR (75 MHz, CDCl3) δ 133.6, 125.7, 125.5, 42.7, 34.5, 30.6, 22.4,
21.9, 13.7, 13.6; MS (EI) m/z (%) 186 (M+, 73), 159 (2), 151 (22),
144 (10), 129 (20), 121 (14), 109 (36), 101 (56), 93 (57), 79 (100),
65 (42), 55 (24); HRMS (EI, ICP, m/z) calcd for C11H1935Cl
186.1175, found 186.1183; IR (film, cm−1) 2959, 2927, 2870, 1659,
1458, 1379, 1339, 1258, 1136, 1091, 1035, 967, 871, 796, 739, 675,
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Note
635, 542. The chloro-functionalized carbon atom could not be
detected in 13C NMR.
chromatography (SiO2, eluent) and bulb-to-bulb distillation to afford 1
and 2 as clear, orange oils.
Credneramide A (1): orange oil; 65 mg (0.20 mmol, 62%); eluent:
pentane diethyl ether = 1:4; 1H NMR (500 MHz, CDCl3) δ 7.31 (t, J
= 7.4 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 7.19 (d, J = 7.0 Hz, 2H), 5.77
(s, 1H), 5.49 (bs, 1H), 5.45 (dt, J = 15.3, 6.4 Hz, 1H), 5.37 (dt, J =
15.1, 6.7 Hz, 1H), 3.52 (dt, J = 7.0, 6.0 Hz, 2H), 2.81 (t, J = 6.9 Hz,
2H), 2.70 (d, J = 6.6 Hz, 2H), 2.32 (dt, J = 7.3, 6.7 Hz, 2H), 2.18 (t, J
= 7.8 Hz, 2H), 2.15 (t, J = 7.8 Hz, 2H), 1.43 (sext, J = 7.8 Hz, 2H),
0.91 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.1, 141.5,
138.9, 131.2, 128.7, 128.6, 127.7, 126.5, 113.1, 40.5, 37.8, 36.3, 35.7,
32.2, 28.3, 20.2, 13.9; MS (EI) m/z (%) 319 (M+, 18), 284 (45), 268
(4), 254 (2), 242 (1), 228 (3), 216 (1), 202 (9), 192 (8), 176 (3), 163
(70), 148 (3), 135 (8), 122 (9), 104 (100), 91 (45), 79 (26), 65 (11),
53 (4); HRMS (APCI, FT-ICR, m/z) calcd for C19H2635ClNOH
320.1776, found 320.1775; IR (film, cm−1) 3287, 3070, 3028, 2958,
2928, 2869, 1714, 1640, 1547, 1449, 1359, 1261, 1196, 1163, 1082,
1032, 969, 922, 849, 792, 744, 697, 570, 497.
(4E,7E)-N-Phenethyl-7-((trimethylsilyl)methylene)dec-4-en-
amide (12a): colorless oil; 268 mg (0.75 mmol, 75%); eluent
1
pentane/diethyl ether = 1:2; H NMR (300 MHz, CDCl3) δ 7.34−
7.29 (m, 2H), 7.25−7.22 (m, 1H), 7.20−7.18 (m, 2H), 5.48−5.33 (m,
3H), 5.16 (s, 1H), 3.52 (q, J = 6.0 Hz, 2H), 2.81 (t, J = 6.9 Hz, 2H),
2.72 (d, J = 4.5 Hz, 2H), 2.36−2.30 (m, 2H), 2.22−2.17 (m, 2H),
2.09−2.04 (m, 2H), 1.47−1.34 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H), 0.08
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 172.4, 158.2, 138.9, 130.1,
129.5, 128.7, 128.6, 126.5, 124.2, 42.1, 40.5, 38.1, 36.6, 35.7, 28.5, 22.1,
14.1, 0.4; MS (EI) m/z 357 (M+, 4), 342 (40), 328 (5), 314 (4), 288
(1), 274 (4), 261 (1), 248 (7), 235 (98), 220 (3), 178 (2), 163 (5),
144 (11), 120 (3), 104 (100), 91 (18), 73 (48), 59 (9); HRMS (EI,
ICP, m/z) calcd for C22H35NOSi 357.2488, found 357.2493; IR (film,
cm−1) 3287, 3077, 3027, 2954, 1642, 1548, 1447, 1361, 1247, 1199,
1152, 1084, 1031, 969, 920, 836, 744, 694, 621, 496.
(4E,7E)-N-Isopentyl-7-((trimethylsilyl)methylene)dec-4-en-
The data are in good accordance to the literature.6
amide (12b): colorless oil; 229 mg (0.71 mmol, 71%); eluent
1
Credneramide B (2): orange oil; 62 mg (0.22 mmol, 66%); eluent
pentane/diethyl ether = 1:2; H NMR (300 MHz, CDCl3) δ 5.52−
1
pentane/diethyl ether = 1:4; H NMR (500 MHz, CDCl3) δ 5.78 (s,
5.36 (m, 3H), 5.17 (s, 1H), 3.26 (td, J = 7.3, 5.6 Hz, 2H), 2.73 (d, J =
5.3 Hz, 2H), 2.39−2.33 (m, 2H), 2.25−2.20 (m, 2H), 2.09−2.04 (m,
2H), 1.67−1.54 (m, 1H), 1.47−1.34 (m, 4H), 0.92−0.87 (m, 9H),
0.08 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 172.3, 158.2, 130.2,
129.5, 124.2, 42.1, 38.6, 38.1, 37.8, 36.7, 28.6, 25.9, 22.4, 22.1, 14.1,
0.4; MS (EI) m/z (%) 323 (M+, 3), 308 (53), 294 (6), 280 (7), 266
(3), 254 (2), 240 (6), 214 (7), 201 (22), 186 (19), 172 (2), 158 (100),
145 (51), 129 (8), 114 (3), 99 (2), 86 (2), 73 (53), 59 (9); HRMS
(APCI, FT-ICR, m/z) calcd for C19H37NOSiH 324.2717, found
324.2716; IR (film, cm−1) 3288, 3086, 2954, 2871, 1641, 1550, 1457,
1367, 1247, 1159, 1069, 1015, 969, 920, 837, 747, 688, 621.
1H), 5.48 (dt, J = 15.4, 6.4 Hz, 1H), 5.41 (dt, J = 16.0, 6.1 Hz, 1H),
5.38 (bs, 1H), 3.26 (dt, J = 7.8, 6.6 Hz, 2H), 2.72 (d, J = 6.4 Hz, 2H),
2.35 (dt, J = 7.2, 7.1 Hz, 2H), 2.21 (t, J = 7.3 Hz, 2H), 2.16 (t, J = 7.3
Hz, 2H), 1.64−1.56 (m, 1H), 1.44 (sext, J = 7.8 Hz, 2H), 1.37 (dt, J =
7.8, 7.1 Hz, 2H), 0.93−0.90 (m, 9H); 13C NMR (125 MHz, CDCl3) δ
172.0, 141.5, 131.3, 127.7, 113.1, 38.6, 37.9, 37.8, 36.4, 32.2, 28.4, 25.9,
22.4, 20.2, 13.9; MS (EI) m/z 285 (M+, 18), 270 (3), 250 (56), 234
(6), 220 (4), 206 (3), 192 (5), 182 (2), 168 (27), 156 (1), 142 (8),
129 (100), 114 (28), 105 (7), 91 (19), 81 (6), 73 (78), 65 (6), 55
(14); HRMS (APCI, FT-ICR, m/z) calcd for C16H2835ClNOH
286.1932, found 286.1931; IR (film, cm−1) 3291, 3082, 2957, 2871,
1640, 1551, 1458, 1367, 1264, 1230, 1162, 969, 793, 717, 594, 507.
The data are in good agreement with the literature.6
Saponification of Methyl Credneroate to Credneric Acid (8).
Following a literature procedure,13 a solution of methyl credneroate
(6) (1.0 equiv) in tetrahydrofuran (0.05 M) was treated with a mixture
of lithium hydroxide (20 equiv) in water (1 M). The solution was
stirred overnight and was then quenched carefully with 5 mL of
aqueous 2 M HCl. The mixture was then transferred into aqueous 0.5
M HCl/ethyl acetate (1:1), and the aqueous phase was extracted three
times with ethyl acetate. The combined organic extracts were dried
over MgSO4 and filtered, and the solvent was evaporated in vacuo.
The residue was purified by flash column chromatography (SiO2,
eluent) and subsequent drying under high vacuum at 50 °C to afford
credneric acid (8) as a yellow oil.
Credneric acid (8): yellow oil; 104 mg (0.48 mmol, 96%); eluent:
diethyl ether; 1H NMR (400 MHz, CDCl3) δ 5.79 (s, 1H), 5.46 (dt, J
= 14.9, 5.9 Hz, 2H), 2.73 (d, J = 6.1 Hz, 2H), 2.43 (t, J = 6.1 Hz, 2H),
2.36 (dt, J = 13.0, 6.1 Hz, 2H), 2.16 (t, J = 7.3 Hz, 2H), 1.44 (sext, J =
7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
179.3, 141.4, 130.5, 128.1, 113.1, 37.9, 33.8, 32.2, 27.4, 20.2, 13.9; MS
(EI) m/z 216 (M+, 24), 180 (7), 163 (26), 156 (33), 145 (6), 135
(16), 127 (18), 121 (100), 113 (13), 107 (41), 101 (11), 91 (89), 85
(1), 79 (91), 73 (4), 67 (25), 60 (6), 53 (18); HRMS (APCI, FT-ICR,
m/z) calcd for C11H1735ClO2H 217.0990, found 217.0989; IR (film,
cm−1) 2960, 2928, 2871, 1706, 1419, 1282, 1212, 1161, 1083, 968,
927, 794, 739, 604, 482.
General Procedure C for the Amidation of 5-Hexenoic Acid.
Following a literature procedure,14 4-N,N-dimethylaminopyridine (30
mol %), triethylamine (2.2 equiv), 5-hexenoic acid (9) (1.0 equiv), and
pivaloyl chloride (1.0 equiv) were dissolved in dichloromethane (0.1
M) and stirred for 1 h at room temperature. Then the respected amine
7a/7b (1.1 equiv) was added, and the reaction mixture was stirred
overnight. After quenching with aqueous 1 M HCl and phase
separation, the organic phase was washed with aqueous NaHCO3
solution and dried over MgSO4 followed by evaporation of the solvent.
The crude product was then purified by flash column chromatography
(silica gel, eluent) to obtain the respective amides 10a/10b as clear
and colorless oils.
Preparation of Methyl Credneroate (6) via Cobalt-Catalyzed
Alder−Ene Reaction. Zinc iodide (40 mol %), zinc powder (40 mol
%), and CoBr2(dppp) (20 mol %) were suspended in acetone (1 M)
under argon atmosphere. Then methyl hex-5-enoate (5) (1.0 equiv)
and 1-chloropent-1-yne (3) (1.0 equiv) were added, and the mixture
was stirred at room temperature for 16 h. The reaction mixture was
treated with additional zinc iodide (40 mol %), zinc powder (40 mol
%), CoBr2(dppp) (20 mol %), and 1-chloropent-1-yne (1.0 equiv) and
was stirred at room temperature for further 16 h. Afterward, the
suspension was filtered over a short pad of silica gel, and the solvent
was removed under vacuum. The residue was purified by flash column
chromatography (SiO2, eluent). The product was accompanied by
small amounts of inseparable methyl hex-5-enoate (purity ∼90 w%).
Methyl credneroate (6): yellow liquid; 103 mg (0.40 mmol,
80%); eluent pentane/diethyl ether = 15:1; 1H NMR (300 MHz,
CDCl3) δ 5.78 (s, 1H), 5.52−5.34 (m, 2H), 3.66 (s, 3H), 2.72 (d, J =
5.5 Hz, 2H), 2.41−2.29 (m, 4H), 2.18−2.12 (m, 2H), 1.43 (sext, J =
7.5 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
173.4, 141.5, 130.9, 127.8, 113.1, 51.5, 37.9, 33.8, 32.2, 27.7, 20.2, 13.9;
MS (EI) m/z (%) 230 (M+, 5), 194 (10), 179 (1), 164 (5), 156 (72),
147 (7), 135 (26), 121 (77), 113 (13), 105 (40), 91 (81), 79 (100), 67
(27), 59 (22), 51 (10); HRMS (APCI, FT-ICR, m/z) calcd for
C12H1935ClO2H 231.1146, found 231.1146; IR (film, cm−1) 2957,
2871, 1737, 1632, 1436, 1358, 1244, 1158, 1086, 1025, 971, 921, 848,
795, 737, 628, 520, 441.
General Procedure B for the Amidation of Methyl
Credneroate (6). Following a literature procedure,12 a solution of
the corresponding amine (7.0 equiv) in dichloromethane (0.77 M)
was treated with trimethylaluminium (5.0 equiv, 1.0 M solution in
heptane) at 0 °C dropwise. The solution was stirred for 30 min at this
temperature. Then a solution of methyl credneroate (1.0 equiv) in
dichloromethane (0.55 M) was injected dropwise at room temper-
ature. The solution was stirred overnight and was then quenched
carefully with aqueous 0.5 M HCl. The mixture was then transferred
into aqueous 0.5 M HCl/dichloromethane (1:1), and the aqueous
phase was extracted three times with dichloromethane. The combined
organic extracts were dried over MgSO4 and filtered, and the solvent
was evaporated in vacuo. The residue was purified by flash column
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The Journal of Organic Chemistry
Note
N-Phenethylhex-5-enamide (10a): white solid; 535 mg (2.46
mmol, 82%); eluent pentane/diethyl ether = 1:2; mp = 48−50 °C; 1H
NMR (300 MHz, CDCl3) δ 7.39−7.23 (m, 5H), 5.81 (td, J = 16.8, 6.8
Hz, 1H), 5.53 (bs, 1H), 5.05 (d, J = 10.4 Hz, 1H), 5.01 (s, 1H), 3.58
(q, J = 6.4 Hz, 2H), 2.87 (t, J = 6.8 Hz, 2H), 2.20−2.08 (m, 4H), 1.76
(qd, J = 7.3, 7.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 172.7, 138.9,
137.9, 128.7, 128.6, 126.5, 115.2, 40.5, 35.9, 35.7, 33.1, 24.7; MS (EI)
m/z 217 (M+, 45), 174 (2), 163 (36), 126 (16), 120 (3), 104 (100),
97 (23), 91 (28), 77 (10), 69 (21), 63 (2), 55 (8); HRMS (EI, ICP,
m/z) calcd for C14H19NO 217.1467, found 217.1464; IR (film, cm−1)
3304, 3067, 3030, 2934, 2870, 1639, 1535, 1451, 1365, 1255, 1208,
1117, 1032, 996, 908, 743, 695, 644, 588, 491.
N-Isopentylhex-5-enamide (10b): colorless oil; 776 mg (4.23
mmol, 85%); eluent pentane/diethyl ether =1: 2; 1H NMR (300 MHz,
CDCl3) δ 5.77 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.46 (bs, 1H), 5.04−
4.95 (m, 2H), 3.25 (td, J = 7.4, 6.0 Hz, 2H), 2.17−2.04 (m, 4H),
1.78−1.68 (m, 2H), 1.67−1.53 (m, 1H), 1.41−1.33 (m, 2H), 0.90 (d, J
= 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 172.6, 137.9, 115.2,
38.6, 37.8, 36.0, 33.1, 25.9, 24.8, 22.4; MS (EI) m/z 183 (M+, 18), 168
(32), 154 (3), 142 (13), 129 (100), 114 (47), 97 (36), 85 (6), 73 (98),
55 (37); HRMS (EI, ICP, m/z) calcd for C11H21NO 183.1623, found
183.1621; IR (film, cm−1) 3288, 3079, 2952, 2870, 1639, 1548, 1448,
1366, 1256, 1164, 993, 910, 683, 454.
General Procedure D for the Chlorodesilylation Reaction.
Following a modified procedure,15 the respective vinylsilane 10 (1.0
equiv) and N-chlorosuccinimide (2.0 equiv) were dissolved in
dimethylformamide (0.038 M) and stirred for 48 h at 30 °C in a
sealed tube. The reaction mixture was then transferred to a 1:1 mixture
of saturated aqueous LiCl solution and diethyl ether. The organic
phase was washed once with brine and then dried over MgSO4. After
filtration and evaporation of the solvent, the crude product was
purified by flash column chromatography (eluent pentane/diethyl
ether = 1: 4) to give the credneramides 1 and 2 as clear orange oils.
Harrity, J. P. A.; Hilt, G. J. Org. Chem. 2010, 75, 3893. (c) Hilt, G.;
Janikowski, J. Org. Lett. 2009, 11, 773.
(3) For a short overview, see: Hilt, G. Synlett 2011, 1654.
(4) Hilt, G.; Treutwein, J. Chem. Commun. 2009, 1395.
(5) Arndt, M.; Reinhold, A.; Hilt, G. J. Org. Chem. 2010, 75, 5203.
(6) Malloy, K. L.; Suyama, T. L.; Engene, N.; Debonsi, H.; Cao, Z.;
Matainaho, T.; Spadafora, C.; Murray, T. F.; Gerwick, W. H. J. Nat.
Prod. 2012, 75, 60.
(7) (a) Trost, B. M.; Machacek, M.; Schnaderbeck, M. J. Org. Lett.
2000, 2, 1761. See also: (b) Cho, E. J.; Lee, D. J. Am. Chem. Soc. 2007,
129, 6692. (c) Trost, B. M.; Papillon, J. P. N.; Nussbaumer, T. J. Am.
Chem. Soc. 2005, 127, 17921. (d) Trost, B. M.; Frederiksen, M. U.;
Rudd, M. T. Angew. Chem., Int. Ed. 2005, 44, 6630. (e) Trost, B. M.
Acc. Chem. Res. 2002, 35, 695. (f) Trost, B. M.; Toste, F. D.;
Pinkerton, A. B. Chem. Rev. 2001, 101, 2067. (g) Trost, B. M.;
Indolese, A.; Muller, T. J. J.; Treptow, B. J. Am. Chem. Soc. 1995, 117,
̈
615.
(8) When 5 was reacted with 3 in the presence of the ruthenium
catalyst, conversions were incomplete and the linear type product
inseparable from unreacted 5. In these cases, the determination of the
products' identity and the ratios formed could not be accomplished
unambiguously. Therefore, 1-hexene was selected as easily removable
alkene component to simulate the behavior of 3. For the preparation
of the 1-chloro-1-pentyne (3), see: (a) Vinczer, P.; Sztruhar, S.; Novak,
L.; Szantay, C. Org. Prep. Proced. Int. 1992, 24, 540. (b) Morse, A. T.;
Leitch, L. C. Can. J. Chem. 1954, 32, 500.
(9) Hilt, G.; Treutwein, J. Angew. Chem., Int. Ed. 2007, 46, 8500.
(10) For another example of altered regioselectivity concerning the
Alder−ene reaction on an ester substituted alkyne, compare the
following references. (a) Trost, B. M.; Martos-Redruejo, A. Org. Lett.
2009, 11, 1071. (b) Hilt, G.; Erver, F.; Harms, K. Org. Lett. 2011, 13,
304.
(11) Hilt, G.; Hengst, C.; Hess, W. Eur. J. Org. Chem. 2008, 2293.
(12) Martín-Couce, L.; Martín-Fontecha, M.; Capolicchio, S.; Lopez
́
-
ASSOCIATED CONTENT
Rodríguez, M. L.; Ortega-Gutierrez, S. J. Med. Chem. 2011, 54, 5265.
́
■
(13) Taber, D. F.; Reddy, P. G.; Arneson, K. O. J. Org. Chem. 2008,
73, 3467.
S
* Supporting Information
1H and 13C NMR spectra for selected compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org
(14) Virolleaud, M.-A.; Menant, C.; Fenet, B.; Piva, O. Tetrahedron
Lett. 2006, 47, 5127.
(15) Graf, K. M.; Tabor, M. G.; Brown, M. L.; Paige, M. Org. Lett.
2009, 11, 5382.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hilt@chemie.uni-marburg.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Fonds der Chemischen Industrie for a fellowship
(F.E.) and the Deutsche Forschungsgemeinschaft for financial
support.
REFERENCES
■
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