Stereocontrolled synthesis of lepadiformine A

Article abstract of DOI:10.1039/b805951a

In this paper we present results of a study into whether the tricyclic core of the lepadiformines A-C can be accessed via intramolecular hetero-Diels-Alder cycloaddition. We are able to demonstrate that such a process is possible and that the reaction proceeds in an endo-selective fashion, providing the correct relative stereochemistry for this family of natural products. By employing this approach we have been able to develop a short (7 step) synthesis of (±)-lepadiformine A, starting from commercially-available trans-2-nonenal.

Full text of DOI:10.1039/b805951a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereocontrolled synthesis of lepadiformine A
Barry Lygo,* Eirene H. M. Kirton and Christopher Lumley
Received 8th April 2008, Accepted 2nd May 2008
First published as an Advance Article on the web 2nd July 2008
DOI: 10.1039/b805951a
In this paper we present results of a study into whether the tricyclic core of the lepadiformines A–C can
be accessed via intramolecular hetero-Diels–Alder cycloaddition. We are able to demonstrate that such
a process is possible and that the reaction proceeds in an endo-selective fashion, providing the correct
relative stereochemistry for this family of natural products. By employing this approach we have been
able to develop a short (7 step) synthesis of ( )-lepadiformine A, starting from commercially-available
trans-2-nonenal.
A further complication is that the Diels–Alder reaction, even if
Introduction
favoured,26 could generate up to four diastereoisomeric products
24. Inspection of simple transition state models leading to each
isomer suggested that the diene should preferentially add anti to
the carboxyl function leading to either 27 or 28 (Fig. 2).
(−)-Lepadiformine A 1 is a tricyclic alkaloid that has been isolated
from several species of sea squirt belonging to the Clavelina and
Polycitoridae families.1–3 It has been shown to be moderately
cytotoxic towards various tumour cell lines, and is also an effective
blocker of cardiac muscle Kir (potassium ion) channels.1,3 The
original structure for this natural product, proposed on the basis
of 1H and 13C NMR analysis,1 was later shown be incorrect, and
the correct relative and absolute stereochemistry was established
by synthesis.4–6 Lepadiformines B and C,3 polycitorals A and B,2
fasicularin,7 and the cylindricines A–K,8 are structurally-related
tricyclic marine alkaloids that have also been isolated from marine
ascidiacea (Fig. 1). Together, this family of natural products
has attracted considerable interest from synthetic chemists,4–6,9–19
culminating in a number of syntheses of lepadiformine A,6,11–17
fasicularin,11,18 and cylindricines A–E.11,14,19
It was less clear whether endo- or exo-mode of addition would be
favoured, so in an effort to gain more insight into this, optimized
transition state structures (gas-phase) for 25 and 26 (R = Me) were
calculated using B3LYP/6-31G*.27 These calculations predict
that both exo- and endo-Diels–Alder reactions would proceed
via highly asynchronous transition states (Fig. 3) and that the
transition state leading to the endo-adduct would be slightly
favoured. Although the predicted energy differences are unlikely
to be accurate for reactions performed in polar media, this
did provide an indication that the desired endo-adduct may be
favoured with this type of substrate.
Encouraged by these results, we moved on to investigate
preparation of the Diels–Alder precursor 20. We considered that
such an intermediate should be readily accessed via Michael
addition of a glycine imine 30 to enone 31 (Scheme 3).
Despite this considerable synthetic effort, as far as we are
aware, there have been no reports of investigations into the use
of an intramolecular hetero-Diels–Alder cycloaddition involving
an imine dieneophile 19 (Scheme 1) as a means of accessing the
tricyclic core 18 of the lepadiformines.
The desired enone 31 was prepared via the sequence outlined in
Scheme 4. Starting from commercially-available trans-2-nonenal
32, Wittig reaction gave diene 33 as a mixture of alkene isomers,
slightly favouring the undesired (6Z,8E)-isomer. This geometrical
mixture could be equilibrated by treatment with iodine and
sunlight, and the pure (6E,8E)-isomer could then be obtained
from the resulting 70 : 30 mixture by repeated crystallization from
petroleum ether at −20 ◦C. In this way we were able to obtain
(6E,8E)-33 in 43% overall yield. This material was then converted
into the desired enone 31 via formation of the Weinreb amide,
followed by reaction with vinylmagnesium bromide. This four-
step sequence provided useful quantities of enone 31.
We next investigated the synthesis of potential Diels–Alder
precursors (Scheme 5). Michael addition of glycine imines 30a and
30b was readily achieved using caesium carbonate in diisopropyl
ether in conjunction with a quaternary ammonium catalyst.28
Hydrolysis of the benzophenone imine, followed by basification29
then led directly to the cyclic imines 35.
This study presents the results of our investigations using the
hetero-Diels–Alder approach to prepare lepadiformine A 1.
Results and discussion
Unconjugated imines tend to be poor dieneophiles, but can
be activated towards Diels–Alder cycloaddition via protonation,
especially if the reaction is carried out in a polar environment.21–23
Thus we envisaged that it may be possible to access the lepad-
iformine A tricycle 24 from an a-carboxy imine precursor 20
(Scheme 2). We considered that under thermal conditions, internal
protonation of the imine function may be sufficient to promote the
desired cycloaddition, and if this proved not to be the case, Diels–
Alder reaction may still be possible via the use of external acid
catalysis. However, there are at least two other thermal processes
that could compete with the desired Diels–Alder reaction; namely
decarboxylation to give imine(s) 22,24 and ene-reaction to give
bicyclic intermediates such as 23.25
We next attempted to perform Diels–Alder cyclizations of
the cyclic imine esters 35a and 35b. Heating either of these
◦
substrates in toluene (up to 165 C) led to slow isomerization of
the 5ꢀ-alkene, but no cycloadducts were formed. Similar results
School of Chemistry, University of Nottingham, Nottingham, UK NG7 2RD
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Scheme 2
Fig. 1 Structures of tricyclic alkaloids isolated from marine ascidiacea.20
Fig. 2
Scheme 1 Possible hetero-Diels–Alder approach to the lepadiformine
tricycle 18.
were obtained when the TFA salt 36 was heated in toluene
(Scheme 6).
Reaction of the corresponding carboxylic acid 20 produced
more interesting results. This substrate was stable towards heating
to 100 ◦C in toluene, but when the temperature was increased to
165 ◦C (sealed tube), decarboxylation was observed, giving rise to a
mixture of imine isomers 22. Attempts to promote the Diels–Alder
pathway by addition of trifluoroacetic acid were unsuccessful;
Fig. 3 B3LYP/6-31G* predicted structures for transition states 25 and
26 (R = Me).
at lower temperatures no reaction occurred, and on heating to
165 ◦C the substrate degraded. We next investigated replacing
toluene with hexafluoroisopropanol. We have previously found
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this to be a highly effective solvent for Diels–Alder chemistry,30
and envisaged that it might provide a sufficiently acidic medium so
as to promote cycloaddition whilst also stabilizing any potential
carboxylate intermediates, such as 21, towards decarboxylation.
This change proved successful; heating imine 20 to 60 ◦C in
this solvent led to formation of the desired cycloadduct 37,
along with a minor diastereoisomer (Scheme 7). At this point
we were unable to unambiguously determine the stereochemistry
of the major product, but subsequent studies (vide infra) have
established that this was the endo-cycloadduct 37 with the correct
relative stereochemistry for lepadiformine A 1. We were unable to
isolate the minor diastereoisomer, consequently this product has
1
not been fully characterized, but H NMR analysis of mixtures
containing this component suggest that it is most probably the
exo-adduct 28 (R = C6H13).
Scheme 3
Scheme 7
Scheme 4 Reagents and conditions: (i) LDA (2.1 eq.), BrPh3P(CH2)5-
CO2H (89%); (ii) I2, hv; (iii) MeNHOMe, EDC, DMAP (94%);
(iv) H2CCHMgBr (79%).
Interestingly, when the cyclic imine ester 35b or the correspond-
ing TFA salt 36 are heated to 60 ◦C in hexafluoroisopropanol, only
very low conversions (>10% after 10 days) to the cycloadducts
are observed. In addition, when acid 20 is heated in less acidic
protic solvents (H2O, MeOH, i-PrOH), no cycloadducts are
observed. This suggests that the combination of the a-carboxyl
group and hexafluoroisopropanol are crucial to the success of this
transformation.
A further advantage of employing hexafluoroisopropanol as
the solvent is that it promotes cleavage of the tert-butyl ester
35a to give the corresponding acid 20 under the same conditions
required for the cycloaddition. Thus, simply by heating ester 35a
in hexafluoroisopropanol at 60 ◦C we were able to obtain the
tricyclic acid 37 in 53% overall yield. This material was readily
converted into ( )-lepadiformine A 1 by hydrogenation of the
alkene followed by reduction of the carboxylic acid using lithium
aluminium hydride (Scheme 8).
Scheme 5 Reagents and conditions: (i) 31, Cs2CO3, i-Pr2O, PhCH2-
NMe3Br; (ii) 15% aq. citric acid, THF; K2CO3 (35a, 77%; 35b, 55%).
Scheme 8 Reagents and conditions: (i) (CF3)2CHOH, 60 ◦C (53%, 5 :
1 mixture of diastereoisomers); (ii) H2, Pd/C, EtOH; (iii) LiAlH4, THF
(52% over two steps).
This study has established that the tricyclic core of lepadi-
formine can be readily accessed via intramolecular cycloaddition
of diene precursor 20. The stereochemical outcome of this
process is consistent with the reaction proceeding via an endo-
selective Diels–Alder reaction. By employing this approach we
have been able to develop a short (7 step) synthesis of ( )-
lepadiformine A 1 starting from commercially-available trans-2-
nonenal.
Scheme 6
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(CH2), 29.4 (CH2), 28.9 (CH2), 28.7 (CH2), 24.2 (CH2), 22.6 (CH2),
14.1 (CH3); m/z (EI) 238.1933 (M+ C15H26O2 requires 238.1933),
238 (100%), 94 (60) and 67 (95).
Experimental
General details
Unless otherwise stated, all solvents and chemicals were used
as provided by the supplier. Reactions were monitored by thin
layer chromatography using Merck silica gel 60 F254 precoated
glass TLC plates, visualised using UV light and then basic
potassium permanganate solution. Flash chromatography was
performed using Merck silica gel (230–400 mesh) as the stationary
phase. Melting points were determined using a Kopfler hot-stage
apparatus and are uncorrected.
Infrared spectra were recorded using either a Perkin-Elmer FT
1600 or a Nicolet Avatar 360 FT-IR infrared spectrophotometer.
1H NMR and 13C NMR spectra were recorded on Bruker AV400 or
DRX500 spectrometers at ambient temperature. Chemical shifts
are quoted relative to residual solvent and J values are given in Hz.
Multiplicities are designated by the following abbreviations: s, sin-
glet; d, doublet; t, triplet; q, quartet; br., broad; m, multiplet. Mass
spectra were obtained on Micromass Autospec or Micromass LCT
instruments using electron impact (EI) or +ve electrospray (ES+).
(6E,8E)-Pentadeca-6,8-dienoic acid methoxymethyl amide.
(6E,8E)-Diene 33 (3.6 g, 15.0 mmol) was dissolved in dry CH2Cl2
(75 mL) and cooled to 0 ◦C and placed under an atmosphere
of nitrogen. N,O-Dimethylhydroxylamine hydrochloride (2.2 g,
22.6 mmol), N-(3-dimethylaminopropyl)-Nꢀ-ethylcarbodiimide
hydrochloride (EDC) (4.4 g, 23.0 mmol) and DMAP (2.8 g,
23.0 mmol) were added to the solution and the mixture was stirred
for 2 h at RT. The reaction was quenched with brine (50 mL)
and the phases separated. The aqueous phase was extracted with
EtOAc (2 × 50 mL) and the combined organics were washed
with 1 M HCl (50 mL), saturated aq. NaHCO3 (50 mL), brine
(50 mL) and dried (MgSO4). The solvent removed under reduced
pressure and the residue was purified by flash chromatography
on silica gel (4 : 1, petroleum ether–EtOAc) to give the Weinreb
amide (3.9 g, 94%) as a yellow oil (found: C, 72.7; H, 11.1; N, 4.6.
C17H31NO2 requires C, 72.55; H, 11.1; N, 5.0%); mmax(neat)/cm−1
3013, 2959, 2854, 1732, 1670, 1462, 1383, 1177, 1109, 988; dH
=
(500 MHz, CDCl3) 6.00–5.97 (2H, m, 2 × C CH), 5.56–5.52
(6E,8E)-Pentadeca-6,8-dienoic acid 33. A solution of freshly
distilled i-Pr2NH (10.7 mL, 76.0 mmol) in dry THF (100 mL) was
placed under an atmosphere of nitrogen, then cooled to −30 ◦C.
n-BuLi (32 mL, 76.0 mmol, 2.4 M) was added dropwise and
the mixture was stirred for 30 min at −30 ◦C. The resulting
LDA solution was added dropwise via cannula to a stirred
suspension of (5-carboxypentyl)triphenylphosphonium bromide
(17.4 g, 36.0 mmol) in dry THF (100 mL) at −30 ◦C under an
atmosphere of nitrogen. The mixture was stirred at RT for 30 min
before re-cooling to −30 ◦C. A solution of freshly distilled trans-
2-nonenal 32 (4.5 mL, 27.0 mmol) in dry THF (50 mL) was then
added dropwise at −30 ◦C. The mixture was then allowed to
warm to RT and stirred for 18 h. An ice-cold solution of 10%
aq. NaHSO4 (200 mL) was added to the mixture and the phases
were separated. The aqueous phase was extracted with Et2O (2 ×
100 mL) and the combined organics were washed with brine
(100 mL) then dried (MgSO4). The solvent was removed under
reduced pressure and the residue extracted with Et2O. Insoluble
Ph3PO was filtered off and the solution was then passed through
a large pad of silica using Et2O (Rf 1), then concentrated under
reduced pressure to give diene 33 (5.6 g, 89%, 60 : 40 mixture
of (6Z,8E)- and (6E,8E)-isomers) as a yellow oil. This material
was then dissolved in chloroform (170 mL), iodine (770 mg,
3.0 mmol) was added, and the mixture was left in natural sunlight
for 4 h. The mixture was washed with saturated aq. Na2S2O3 (2 ×
100 mL), the combined organics were dried (MgSO4) and the
solvent removed under reduced pressure to give the crude diene 33
as a 30 : 70 mixture of (6Z,8E)- and (6E,8E)-isomers. Repeated
recrystallization from petroleum ether (cooling to −20 ◦C and then
filtering the crystals ice cold) gave the (6E,8E)-isomer 33 (2.4 g,
43%) as a low-melting solid (found: C, 75.6; H, 10.95. C15H26O2
requires C, 75.6; H, 11.00%); mmax(neat)/cm−1 3014, 2955, 2920,
2848, 1712, 1444, 1308, 1254, 1202, 980, 902; dH (500 MHz, CDCl3)
=
(2H, m, 2 × C CH), 3.66 (3H, s, OCH3), 3.17 (3H, s, NCH3),
2.41 (2H, t, J 7.5, CH2CO), 2.10–2.01 (4H, m), 1.66–1.60 (2H, m),
1.45–1.36 (2H, m), 1.36–1.23 (8H, m), 0.87 (3H, t, J 7.0, CH3); dC
(100 MHz, CDCl3) 174.5 (C), 132.5 (CH), 131.5 (CH), 130.7 (CH),
130.1 (CH), 61.1 (CH3), 32.5 (CH2), 32.2 (CH3), 32.1 (CH2), 31.6
(CH2), 31.5 (CH2), 29.3 (CH2), 29.1 (CH2), 28.8 (CH2), 24.1 (CH2),
22.5 (CH2), 14.1 (CH3); m/z (ES+) 282.2437 (M + H+ C17H32NO2
requires 282.2433), 282 (100%).
(6E,8E)-Heptadeca-1,8,10-triene-3-one 31. (6E,8E)-Penta-
deca-6,8-dienoic acid methoxymethyl amide (3.9 g, 14.0 mmol)
was dissolved in dry THF (200 mL), placed under an atmosphere
of nitrogen, and cooled to −78 ◦C. Vinylmagnesium bromide
(41 mL of a 1 M solution in Et2O, 41.0 mmol) was added
dropwise. The mixture was stirred for 30 min then allowed to
warm to RT and stirred for a further 4 h. Aqueous HCl (200 mL,
1 M) was added and the phases separated. The aqueous phase was
extracted with EtOAc (2 × 150 mL) and the combined organics
were washed with brine (150 mL) and dried (MgSO4). The
solvent was removed under reduced pressure and the residue was
purified by flash chromatography on silica gel (6 : 1, petroleum
ether–EtOAc) to give the enone 31 (2.7 g, 79%) as a yellow oil
(found: C, 82.2; H, 11.3. C17H28O requires C, 82.2; H, 11.4%);
mmax(neat)/cm−1 3014, 2926, 2855, 1703, 1683, 1615, 1456, 1401,
987, 725; dH (500 MHz, CDCl3) 6.34 (1H, dd, J 17.5, 10.5,
=
=
CH CH2), 6.21 (1H, dd, J 17.5, 1.0, C CHaHb), 6.03–5.95 (2H,
=
=
m, 2 × C CH), 5.81 (1H, dd, J 10.5, 1.0, C CHaHb), 5.59–5.51
=
(2H, m, 2 × C CH), 2.58 (2H, t, J 7.5, CH2CO), 2.17–2.02 (4H,
m), 1.66–1.60 (2H, m), 1.44–1.22 (10H, m), 0.88 (3H, t, J 7.0,
CH3); dC (100 MHz, CDCl3) 200.8 (C), 136.6 (CH), 132.8 (C),
131.5 (C), 130.8 (C), 130.1 (C), 127.9 (C), 39.5 (CH2), 32.6 (CH2),
32.3 (CH2), 31.7 (CH2), 29.4 (CH2), 29.0 (CH2), 28.9 (CH2), 23.5
(CH2), 22.6 (CH2), 14.1 (CH3); m/z (EI) 248.2143 (M+ C17H28O
requires 248.2140), 248 (40%), 207 (20), 123 (25), 79 (80), 67 (100).
=
=
6.04–5.97 (2H, m, 2 × C CH), 5.61–5.52, (2H, m, 2 × C CH),
2.37 (2H, t, J 7.5, CH2CO2H), 2.11–2.03 (4H, m), 1.69–1.63 (2H,
m), 1.48–1.40 (2H, m), 1.38–1.24 (8H, m), 0.89 (3H, t, J 7.0,
CH3); dC (100 MHz, CDCl3) 179.8 (C), 132.9 (CH), 131.3 (CH),
130.9 (CH), 130.1 (CH), 33.8 (CH2), 32.6 (CH2), 32.1 (CH2), 31.7
(5E,7E)-5-Tetradeca-5ꢀ,7ꢀ-dienyl-3,4-dihydro-2H-pyrrole-2-car-
boxylic acid tert-butyl ester 35a. Enone 31 (208 mg, 0.84 mmol)
was added to a solution of glycine imine 30a (247 mg, 0.84 mmol)
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and benzyltrimethylammonium bromide (19 mg, 0.08 mmol) in
diisopropyl ether (15 mL). Cs2CO3 (547 mg, 1.68 mmol) was
then added and the mixture stirred at RT overnight. The reaction
mixture was filtered through MgSO4 and then concentrated under
reduced pressure the give the crude imine 34a (484 mg) as a yellow
oil; dH (400 MHz, CDCl3) 7.84–7.21 (10H, m, ArH), 6.04–5.96
m), 0.92 (3H, t, J 7.0, CH3); dC (100 MHz, CD3OD, peaks for
major diastereoisomer only) 172.8 (C), 139.4 (CH), 126.8 (CH),
79.0 (CH), 67.7 (CH), 58.6 (C), 42.7 (CH2), 33.0 (CH2), 31.3 (CH2),
30.4 (CH2), 28.8 (CH2), 28.2 (CH2), 28.0 (CH2), 27.1 (CH2), 25.9
(CH2), 24.6 (CH2), 23.3 (CH2), 22.2 (CH2), 13.0 (CH3); m/z (ES+)
306.2425 (M + H+ C19H32NO2 requires 306.2433) 306 (100%).
=
=
(2H, m, 2 x CH CH), 5.62–5.50 (2H, m, 2 x CH CH), 3.96 (1H,
apparent t, J 7.0, CH2), 2.60–2.46 (2H, m), 2.41 (2H, apparent t,
J 7.5, CH2), 2.25–2.03 (6H, m), 1.46 (9H, s, C(CH3)3), 1.61–1.25
(12H, m), 0.85 (3H, t, J 6.5, CH3). This material was dissolved in
a mixture of THF (10 mL) and 15% aq. citric acid (10 mL) and
stirred at room temperature for 3 h. The mixture was basified with
solid K2CO3 and stirred for a further 30 min. CH2Cl2 (30 mL)
was then added and the phases separated. The aqueous phase
was extracted with CH2Cl2 (30 mL) and the combined organics
dried (MgSO4) and then concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(4 : 1, petroleum ether–Et2O) to give the cyclic imine 35a (235 mg,
77%) as a pale yellow oil; mmax(neat)/cm−1 2926, 2855, 1734, 1642,
1457, 1367, 1256, 1211, 1155, 987; dH (400 MHz, CDCl3) 6.02–
Hydrogenation of cycloadduct 37. A solution of the alkene
37 (30 mg, 0.097 mmol) in EtOH (4 mL) was treated with 10%
Pd/C (30 mg) and the mixture stirred at RT overnight under an
atmosphere of hydrogen (balloon). The mixture was then filtered
through Celite and then concentrated under reduced pressure to
give the crude acid (30 mg, 100%) as a white solid; mmax(neat)/cm−1
3404, 2929, 2858, 1629, 1466; dH (400 MHz, CD3OD, peaks
for major diastereoisomer only) 4.07 (1H, apparent t, J 10.0,
CHCO2H), 3.75–3.72 (1H, m, CHN), 2.55–2.38 (1H, m), 2.20–
1.15 (26H, m), 0.93–0.87 (3H, m); dC (100 MHz, CD3OD, peaks for
major diastereoisomer only) 76.7 (CH), 63.7 (C), 57.6 (CH), 36.2
(CH2), 34.5 (CH2), 31.3 (CH2), 30.0 (CH2), 29.7 (CH2), 28.9 (CH2),
27.8 (CH2), 27.4 (CH2), 25.7 (CH2), 25.0 (CH2), 23.1 (CH2), 22.2
(CH2), 21.6 (CH2), 19.0 (CH2), 13.0 (CH3); m/z (ES+) 308.2582
(M + H+ C19H34NO2 requires 308.2584) 308 (100%). This material
was used directly in the next step without further purification.
=
=
5.94 (2H, m, 2 x CH CH), 5.57–5.46 (2H, m, 2 x CH CH),
4.55 (1H, apparent t, J 7.0, CHN), 2.68–2.41 (2H, m), 2.38 (2H,
m), 2.18–1.81 (6H, m), 1.46 (9H, s, C(CH3)3), 1.46–1.25 (12H,
m), 0.85 (3H, t, J 7.0, CH3); dC (100 MHz, CDCl3) 181.5 (C),
172.6 (C), 132.7 (CH), 131.7 (CH), 130.7 (CH), 130.2 (CH),
80.9 (C), 74.8 (CH), 37.5 (CH2), 33.7 (CH2), 32.6 (CH), 32.3 (CH2),
31.8 (CH2), 29.4 (CH2), 28.9 (CH2), 28.0 (CH3), 26.7 (CH2), 26.0
(CH2), 22.7 (CH2), 14.1 (CH3); m/z (ES+) 362.3064 (M + H+
C23H40NO2 requires 362.3059) 362 (100%), 306 (50).
Lepadiformine A 1. The crude acid from above (30 mg,
0.097 mmol) was dissolved in THF (4 mL) and placed under an
atmosphere of nitrogen. LiAlH4 (0.24 mL of a 2.4 M solution in
THF, 0.59 mmol) was added dropwise and the reaction heated
at reflux for 4 h. The reaction was then cooled to 0 ◦C and
water saturated diethyl ether added (5 mL, 0.58 M water in
Et2O), the reaction was then allowed to warm to RT and water
added (5 mL). The aqueous layer was extracted with EtOAc
(3 × 10 mL) and the combined organics dried (MgSO4) and then
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (75 : 4.5 : 1, CH3Cl–CH3OH–
NH4OH) to give the lepadiformine A 1 (15 mg, 52%) as a clear
oil; dH (400 MHz, CDCl3) 3.43–3.32 (2H, m), 3.24 (1H, d, J 8.5),
3.20–3.13 (1H, m), 1.86–1.14 (27H, m), 1.10–0.97 (1H, m), 0.89
(3H, t, J 6.5, CH3); dC (100 MHz, CDCl3) 67.5 (C), 62.3 (CH),
58.5 (CH), 53.4 (CH), 40.0 (CH2), 38.3 (CH2), 34.1 (CH2), 31.9
(CH2), 30.6 (CH2), 29.6 (CH2), 28.2 (CH2), 27.7 (CH2), 27.6
(CH2), 26.3 (CH2), 24.3 (CH2), 23.3 (CH2), 22.7 (CH2), 14.1 (CH3);
m/z (ES+) 294.2769 (M + H+ C19H36NO requires 294.2793) 294
(100%). The above 1H NMR and 13C NMR data is in agreement
with that previously reported.12
(5E,7E)-5-Tetradeca-5ꢀ,7ꢀ-dienyl-3,4-dihydro-2H-pyrrole-2-car-
boxylic acid benzyl ester 35b. Glycine imine 30b (257 mg,
0.78 mmol) was reacted with enone 31 following the above
procedure to give the cyclic imine 35b (170 mg, 55%) as a pale
yellow oil; (found: C, 78.8; H, 9.3; N, 3.4. C26H37NO2 requires C,
78.9; H, 9.4; N, 3.5%); mmax(neat)/cm−1 3013, 2926, 2855, 1741,
1640, 1456, 1379, 1342, 1264, 1171, 988, 735, 697; dH (400 MHz,
=
CDCl3) 7.37–7.30 (5H, m, ArH), 6.01–5.94 (2H, m, 2 x CH CH),
5.60–5.49 (2H, m, 2 x CH CH), 5.22 (1H, d, J 12.0, CHaHbPh),
=
5.19 (1H, d, J 12.0, CHaHbPh), 4.74–4.69 (1H, m, CHN), 2.65–
2.60 (1H, m), 2.56–2.49 (1H, m), 2.41 (2H, apparent t, J 7.5, CH2),
2.23–2.13 (1H, m), 2.14–2.00 (5H, m), 1.64–1.58 (2H, m), 1.46–
1.26 (10H, m), 0.88 (3H, t, J 7.5, CH3); dC (100 MHz, CDCl3)
182.3, 172.9, 135.8, 132.8, 131.6, 130.8, 130.2, 128.6, 128.5, 128.2,
128.2, 73.9, 66.6, 37.6, 33.6, 32.6, 32.3, 31.8, 29.4, 29.1, 28.9, 26.4,
25.9, 22.6, 14.1; m/z (ES+) 396.2904 (M + H+ C26H38NO2 requires
396.2903) 396 (100%), 306 (50).
Acknowledgements
Diels–Alder reaction of 35a. A solution of the cyclic imine 35a
(29 mg, 0.08 mmol) in degassed (5 freeze–thaw cycles) 1,1,1,3,3,3-
hexafluoropropan-2-ol (1.5 mL) in a sealed tube was placed under
an atmosphere of argon and heated at 60 ◦C for 9 days and then
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (9 : 1, CH2Cl2–MeOH) to give
the cycloadduct 37 (13 mg, 53%, 5 : 1, mixture diastereoisomers)
as a pale yellow oil; dH (500 MHz, CD3OD, peaks for major
Financial support for this work was provided by EPSRC.
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