Transannular dipolar cycloaddition as an approach towards the synthesis of the core ring system of the sarain alkaloids

Article abstract of DOI:10.1039/c0ob01019g

Intramolecular transannular dipolar cycloaddition was investigated as a key step in a synthetic approach to the core of the sarain alkaloids; although the use of an azomethine ylide was unsuccessful with the chosen aldehyde substrate, cycloaddition with a

Full text of DOI:10.1039/c0ob01019g

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PAPER
Transannular dipolar cycloaddition as an approach towards the synthesis of
the core ring system of the sarain alkaloids†
Andrew I. Franklin, David Bensa, Harry Adams and Iain Coldham*
Received 11th November 2010, Accepted 13th December 2010
DOI: 10.1039/c0ob01019g
Intramolecular transannular dipolar cycloaddition was investigated as a key step in a synthetic
approach to the core of the sarain alkaloids; although the use of an azomethine ylide was unsuccessful
with the chosen aldehyde substrate, cycloaddition with a nitrone did give the alternative regioisomeric
bridged cycloadduct.
have reported an approach that relies on an intermolecular [4+3]
Introduction
cycloaddition of cyclopentadiene and an oxyallyl cation.6 Two
The sarain alkaloids, sarain A, B and C, consist of a unique
different strategies using conjugate addition chemistry to give a
polycyclic ring system containing a tricyclic core and two macro-
bicyclic system that was elaborated to the tricyclic core have been
reported by Mons and Marazano and co-workers7 and by Yang
and Huang.8 Porter has investigated an approach using aminals.9
Our interest in the synthesis of the marine alkaloid manzamine
A using an intramolecular cycloaddition of an azomethine ylide
as a key step10 prompted us to investigate a new and efficient
approach to the sarain alkaloids. Our retrosynthetic analysis
is shown in Scheme 1. Disconnection of the macrocyclic rings
suggested that the tricyclic core 1 would be a suitable target [a
cyclic tethers with a zwitterionic structure due to the promixity
of a tertiary amine and an aldehyde group (Fig. 1). These
natural products were isolated in 1989 from the marine sponge
Reniera sarai, and were shown to possess moderate anticancer,
antibacterial and insecticidal activity.1 The sarains are thought
to derive biosynthetically from the reductive condensation of a
bispyridinium macrocycle.2 Their fascinating structures together
with their biological activity has led to several synthetic endeavors
in this area. So far, there is one reported synthesis of sarain A,
by Overman and co-workers, that uses a cyclization of a silyl
enol ether onto an iminium ion to set up the core tricyclic ring
system.3 The groups of Heathcock and Weinreb independently
reported the use of aziridines as azomethine ylide precursors
that undergo cycloaddition to access a bicyclic ring system.4,5
Subsequent cyclization of an allyl silane onto an iminium ion has
provided the desired bridged tricyclic core. Cha and co-workers
t
variety of heteroatom substituents R, R¢, Boc (= CO2 Bu) could
be chosen]. Our plan was to access this core directly from the
azomethine ylide 2. Transannular dipolar cycloaddition reactions
of azomethine ylides are rare, although one example across a
seven-membered ring has been reported.11 The ylide 2 could be
constructed in situ from the condensation of an aldehyde such as
3 (or 4) and an amine.12 In this paper we report the results of our
efforts using this strategy.
Fig. 1 Sarain alkaloids.
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, UK
S3 7HF. E-mail: i.coldham@sheffield.ac.uk; Fax: +44 (0)114 222 9436;
Tel: +44 (0)114 222 9428
Scheme 1 Disconnection approach to the core ring system.
† Electronic supplementary information (ESI) available: Procedures and
data for compounds 9 to 21; crystallographic information and ORTEP
diagrams for the alcohol 8 and the amide 23. (CCDC reference numbers
791948 and 791949 respectively). For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c0ob01019g
Results and Discussion
The synthesis of the aldehyde 4 is shown in Schemes 2 and 3
and started with the enantiomerically pure lactone 5 (available
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14 with sarcosine ethyl ester but this also gave a mixture of
products.
As an alternative substrate, we alkylated the oxazolidinone 10
to give the oxazolidinone 15 (Scheme 4). This compound was
subjected to ring-closing metathesis to give the 8-membered ring
product 16. Hydrolysis of the oxazolidinone 16 gave the amino-
alcohol 17 which was protected as the N-Boc derivative 18. Finally,
oxidation of the alcohol gave the aldehyde 19 (akin to 3).
Scheme 2 Preparation of oxazolidinones 9 and 10. Reagents and condi-
tions: i, NaOEt, EtOH, r.t., 72%; ii, 2 equiv. NaHMDS, THF, -78 ◦C,
allyl bromide, 70%; iii, Ca(BH4)2 (or LiBH4), EtOH, r.t., 85% (or 77%);
iv, Cl3CC( NH)OR, CH2Cl2, 20 mol% TMSOTf or 10 mol% camphor
sulfonic acid, r.t., 18 h, R = Bn 79%, or R = PMB 81%.
Scheme 4 Preparation of aldehyde 19. Reagents and conditions: i,
NaOH(s), PhMe, K2CO3, Bu4NHSO4, heat, 1 h, 99%; ii, 2 ¥ 3.3 mol%
Cl2(PCy3)[(CH2NMes)2C]Ru CHPh, PhMe, 40 ◦C, 2.5 h, 73%; iii,
NaOH, EtOH, H2O, 80 ◦C, 18 h, 95%; iv, Boc2O, dioxane, H2O, NaHCO3,
98%; v, Dess–Martin periodinane, CH2Cl2, 0 ◦C, 2 h, 86%.
Unfortunately, we found that no discernable reaction took place
on heating the aldehyde 19 with the amino-acid sarcosine or
sarcosine ethyl ester or glycine ethyl ester in various solvents
(PhMe, dioxane, D◦MF). At higher temperatures (130 ◦C, PhMe,
sealed tube or 215 C, DMF, microwave heating) decomposition
occurred. We were able to show that the azomethine ylide was
being formed by heating the aldehyde 19 with sarcosine in the
presence of the dipolarophile N-methylmaleimide (Scheme 5).
This gave a mixture of four diastereomeric products 20 from
intermolecular cycloaddition.
Scheme 3 Preparation of aldehyde 14. Reagents and conditions: i, KH,
PMBCl, 10 mol% Bu4NI, THF, r.t., 22 h, 79%; ii, allyl magnesium
bromide (2 equiv.), THF, -78 ◦C, 2.5 h, 63%; iii, 2 ¥ 5 mol%
Cl2(PCy3)[(CH2NMes)2C]Ru CHPh, ClCH2CH2Cl, 80 ◦C, 9 h, 58%; iv,
Dess–Martin periodinane, CH2Cl2, 0 ◦C, 2 h, 60%.
commercially but alternatively prepared from N-carboxybenzyl
aspartic acid).13 Treatment of the lactone 5 with sodium ethoxide
gave the oxazolidinone 6, which was deprotonated and alkylated
with allyl bromide to give a single diastereomer of the product 7.14
The high selectivity is thought to be a result of conformational
effects arising from chelation of the ester sodium enolate with the
(deprotonated) oxazolidinone nitrogen atom.14 Reduction of the
ester (in the presence of the oxazolidinone using calcium or lithium
borohydride) and protection of the alcohol 8 gave the products 9
and 10. The relative stereochemistry of the alcohol 8 was verified
by single crystal X-ray diffraction (see ESI†).
The oxazolidinone 9 was protected to give the oxazolidinone 11,
which was subjected to ring-opening with allyl magnesium bro-
mide to give the amide 12 (Scheme 3).15 Ring-closing metathesis16
then gave the 8-membered ring product 13 and oxidation of the
alcohol gave the aldehyde 14 (akin to 4).
With one of the desired aldehydes in hand, we attempted some
cycloaddition reactions. There are various methods reported for
theformation of azomethine ylides.12 To generate a ‘non-stabilized’
ylide, one method involves decarboxylation of an intermediate
oxazolidinone formed from an aldehyde and an amino-acid.17 On
heating the aldehyde 14 with the amino-acid sarcosine (N-methyl
glycine) in toluene, an inseparable mixture of many products was
obtained. To generate the stabilized ylide, we heated the aldehyde
Scheme 5 Intermolecular cycloaddition using the aldehyde 19. Reagents
and conditions: i, MeHNCH2CO2H, N-methylmaleimide, DMF, heat, 18 h,
77%.
We were disappointed that no transannular dipolar cycloaddi-
tion of the azomethine ylides took place. This may be compounded
by the unactivated nature of the alkene (electron-withdrawing
groups are known to promote such cycloadditions).12 We were keen
to demonstrate that dipolar cycloaddition was possible and were
aware that nitrones are typically more amenable to cycloaddition
with a range of alkene dipolarophiles.18 Therefore, we heated the
aldehyde 19 with N-methyl-hydroxylamine and were pleased to
find that a single product was formed (65% yield as an oil) that had
the desired mass and no longer contained the alkene functional
group (see ESI†). We were unable to determine the regiochemistry
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of the cycloaddition from the spectroscopic data and attempts to
deprotect the Boc and/or PMB groups with acid gave a very polar
product that did not provide any desired amide or ester products
after acylation. Therefore, to avoid problems with concommitant
deprotection of both the Boc and PMB groups, we converted the
oxazolidinone 9 through the same sequence as performed with
oxazolidinone 10 (shown in Scheme 4). This gave the analogous
aldehyde 21 with which we carried out the same cycloaddition
reaction using N-methyl-hydroxylamine (Scheme 6).
using this approach, further work will be required to direct the
regiochemistry and also allow cycloaddition of the azomethine
ylide, possibly by activating the alkene dipolarophile with a
suitable electron-withdrawing group.
Experimental
General methods
For general experimental details, including information on solvent
purifications and the spectrometers used in this research, see
previous descriptions.19 For procedures and spectroscopic data
for compounds not reported below, together with crystallographic
data for the alcohol 8 and the amide 23, see ESI.†
(S)-Ethyl 2-(2-oxo-oxazolidin-4-yl)acetate 6. Freshly prepared
NaOEt (1.0 M, 85 mL, 85 mmol) was added to lactone 520 (8 g,
34 mmol) in EtOH (170 mL) at room temperature. After 2 h, HCl
(1.0 M, 85 mL) was added and the mixture was extracted with
CH2Cl2 (3 ¥ 100 mL), dried (MgSO4) and evaporated. Purification
by column chromatography on silica, eluting with EtOAc–Et2O
(1 : 4 to 3 : 2), gave the oxazolidinone 6 (4.2 g, 72%) as an oil;
Scheme 6 Nitrone cycloaddition using the aldehyde 21. Reagents and
conditions: i, MeNHOH·HCl, EtOH, NaHCO3, sealed tube, 125 ◦C, 4 h,
73% (22a).
We were pleased to find that a single cycloadduct was formed
(73% yield), although once again we were unclear as to the
regiochemistry of the cycloaddition reaction (product 22a or 22b).
Removal of the N-Boc group with TFA and treatment with p-
bromobenzoyl chloride gave a crystalline product, for which X-ray
crystal structure analysis indicated the structure 23 (Fig. 2).
1
[a]D20 -14.2 (2.3, MeOH); vmax/cm-1 3285, 1750, 1720; H NMR
(250 MHz, C6D6) d = 6.16–5.99 (br, 1H), 3.80 (q, 2H, J 7 Hz), 3.68
(t, 1H, J 8 Hz), 3.36–3.25 (m, 1H), 3.22 (dd, 1H, J 8, 6 Hz), 1.83
(dd, 1H, J 17, 7.5 Hz), 1.62 (dd, 1H, J 17, 5.5 Hz), 0.88 (t, 3H, J
7 Hz); 13C NMR (75 MHz, CDCl3) d = 170.4, 159.1, 69.4, 61.2,
48.9, 39.6, 14.5; HRMS (EI) found 173.0689, C7H11NO4 requires
(M) 173.0688; m/z (EI) 173 (5%), 129 (45), 86 (100); Found: C,
48.82; H, 6.55; N, 7.89; C7H11NO4 requires C, 48.55; H, 6.40; N,
8.09%. Compound 6 has been reported, but no characterization
data were given.14
(R)-Ethyl 2-[(S)-2-oxo-oxazolidin-4-yl]pent-4-enoate 7. Oxa-
zolidinone 6 (0.2 g, 1.2 mmol) in THF (3 mL) was added to
◦
NaN(TMS)2 (0.47 g, 2.43 mmol) in THF (6 mL) at -78 C over
5 min. After 1 h, allyl bromide (0.2 mL, 2.4 mmol) in THF (3 mL)
was added over 5 min and the mixture was warmed to -40 ◦C. After
4 h, saturated NH4Cl solution (20 mL) was added, the mixture was
extracted with CH2Cl2 (3 ¥ 20 mL), dried (MgSO4) and evaporated.
Purification by column chromatography on silica, eluting with
EtOAc–petrol (1 : 5 to 1 : 0), gave the oxazolidinone 7 as a single
Fig. 2 X-ray structure of 23 (Ar = C6H4-p-Br), derived from 22a.
The compound 23 must have derived from the cycloadduct
22a (rather than 22b), thereby showing that the cycloaddition of
the nitrone (derived from aldehyde 21) had occurred to give the
undesired regiochemistry. After removal of the N-Boc group from
22a and treatment with p-bromobenzoyl chloride, the amide 23
must have formed by acylation of both nitrogen atoms, together
with breakage of the N–O bond and N-demethylation. It is not
clear how this occurs, but one possibility is that acylation of
the tertiary amine gives a quaternary ammonium salt that could
fragment (N–O bond breakage) to give an iminium ion that
hydrolyses to the secondary amide.
diastereoisomer (0.18 g, 70%) as an oil; [a]2D0 -24.5 (2.5, CHCl3);
1
v
max/cm-1 3255, 1750, 1720, 1640; H NMR (400 MHz, CDCl3)
d = 6.31–6.24 (br, 1H), 5.68 (ddt, 1H, J 17, 10, 7.5 Hz), 5.14–5.05
(m, 2H), 4.46 (t, 1H, J 8.5 Hz), 4.21–4.14 (m, 3H), 4.11–4.06 (m,
1H), 2.64 (td, 1H, J 7.5, 5.5 Hz), 2.43–2.28 (m, 2H), 1.26 (t, 3H, J
7 Hz); 13C NMR (100 MHz, CDCl3) d = 172.4, 159.2, 133.3, 118.4,
67.9, 61.3, 52.8, 49.5, 32.4, 14.1; HRMS (EI) found 213.0999,
C10H15NO4 requires (M) 213.1001; m/z (EI) 213 (20), 171 (50),
128 (100); Found: C, 56.03; H, 7.28; N, 6.32; C10H15NO4 requires
C, 56.33; H, 7.09; N, 6.57%. Compound 7 has been reported, but
no characterization data were given.14
(S)-4-[(R)-1-Hydroxypent-4-en-2-yl]oxazolidin-2-one
NaBH4 (0.92 g, 24 mmol) was added to oxazolidinone 7
8.
Conclusions
We have shown that a transannular dipolar cycloaddition onto
an unactivated alkene in an eight-membered ring is possible
using a nitrone, but not using an azomethine ylide. This led to
the undesired regioisomer of the bridged tricyclic product. To
form the desired pyrrolidine ring present in the sarain alkaloids
(0.43 g, 2 mmol) and dry CaCl2 (1.34 g, 12 mmol) in dry EtOH
(63 mL) at 0 C and the mixture was allowed to warm to room
temperature. After 16 h, saturated CaCO3 (23 mL) and sodium
potassium tartrate (62 mL, 1.0 M) were added. The mixture
was extracted with EtOAc (3 ¥ 60 mL), dried (MgSO4) and
◦
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evaporated. Purification by column chromatography on silica,
eluting with EtOAc–pe◦trol (7 : 3), gave the alcohol 8 (0.29 g, 85%)
as needles; m.p. 57–58 C; [a]2D0 9.3 (2.5, MeOH); vmax/cm-1 3350,
2960, 2870, 1725; 1H NMR (250 MHz, CDCl3) d = 6.97–6.90 (br,
1H), 5.91–5.63 (m, 1H), 5.11–5.02 (m, 2H), 4.47 (t, 1H, J 8.5 Hz),
4.20–4.13 (m, 1H), 3.96–3.89 (m, 1H), 3.75 (dd, 1H, J 11, 4 Hz)
3.59 (dd, 1H, J 11, 6 Hz), 3.56–3.39 (br, 1H), 2.07–2.00 (m, 2H),
1.77–1.71 (m, 1H); 13C NMR (63 MHz, CDCl3) d = 160.5, 135.1,
117.6, 69.5, 62.2, 54.7, 44.5, 31.9; HRMS (EI) found 172.0973,
C8H14NO3 requires (MH) 172.0970; m/z (EI) 172 (10%), 140
(100); Found: C, 55.79; H, 7.58; N, 8.09; C8H13NO3 requires C,
56.13; H, 7.65; N, 8.18%.
After 20 min, the mixture was cooled to room temp. and n-Bu4NI
(330 mg, 0.88 mmol) and p-methoxybenzyl chloride (1.37 mL,
10.1 mmol) were added. After 22 h, brine (15 mL) was added and
the mixture was extracted with EtOAc (3 ¥ 20 mL). The combined
organic extracts were washed with brine, dried (Na2SO4), filtered
and evaporated. Purification by column chromatography on
silica, eluting with EtOAc–petrol (1 : 4), gave the oxazolidinone
11 (1.73 g, 79%) as an oil; [a]2D2 +18.2 (0.55, CH2Cl2); vmax/cm-1
2905, 1740; 1H NMR (250 MHz, CDCl3) d = 7.34–7.11 (m, 5H),
7.14 (d, 2H, J 8.5 Hz), 6.83 (d, 2H, J 8.5 Hz), 5.64–5.44 (m,
1H), 5.03–4.89 (m, 2H), 4.67 (d, 1H, J 15 Hz), 4.35 (ABq, 2H, J
12 Hz), 4.20–4.13 (m, 2H), 4.02 (d, 1H, J 15 Hz), 3.85 (td, 1H,
J 7.5, 2 Hz), 3.77 (s, 3H), 3.40–3.26 (m, 2H), 2.10–1.91 (m, 3H);
13C NMR (63 MHz, CDCl3) d = 159.0, 158.6, 137.6, 135.3, 129.3,
128.1, 127.7, 127.5, 127.2, 116.9, 113.9, 72.9, 68.8, 63.7, 56.2,
55.0, 45.5, 37.9, 28.2; HRMS (ES) found 404.1843, C23H27NO4Na
requires (MNa) 404.1838; Found: C, 72.60; H, 7.00; N, 3.38;
C23H27NO4 requires C, 72.42; H, 7.13; N, 3.67%.
(S)-4-[(R)-1-(Benzyloxy)pent-4-en-2-yl]oxazolidin-2-one
9.
TMSOTf (0.29 mL, 1.63 mmol) was added to the alcohol 8 (1.4 g,
8.2 mmol) and benzyl t◦richloroacetimidate (1.6 mL, 9.0 mmol) in
CH2Cl2 (140 mL) at 0 C and the mixture was allowed to warm
to room temperature. After 18 h, the solvent was evaporated and
the mixture was purified by column chromatography on silica,
eluting with EtOAc–petrol (1 : 3), to give the ether 9 (1.3 g, 79%)
as an oil; [a]D22 -6.0 (0.5, CH2Cl2); vmax/cm-1 3260, 2910, 2860,
1740, 1640; 1H NMR (250 MHz, CDCl3) d = 7.35–7.20 (m, 5H),
5.92 (br, 1H), 5.77–5.60 (m, 1H), 5.10–5.00 (m, 2H), 4.56–4.39
(m, 3H), 4.17 (dd, 1H, J 8.5, 7 Hz), 3.90 (q, 1H, J 7 Hz), 3.55
(dd, 1H, J 9.5, 4 Hz), 3.44 (dd, 1H, J 9.5, 6.5 Hz), 2.05 (t, 2H, J
7 Hz), 2.00–1.75 (m, 1H); 13C NMR (63 MHz, CDCl3) d = 159.9,
137.9, 135.0, 128.5, 127.8, 127.7, 117.7, 73.4, 70.2, 68.8, 54.9,
42.6, 31.8; HRMS (ES) found 284.1253, C15H19NO3Na requires
(MNa) 284.1263; m/z (ES) 284 (100%), 262 (22).
But-3-enoic acid [(1S,2R)-2-benzyloxymethyl-1-hydroxymethyl-
pent-4-enyl]-(4-methoxybenzyl)amide 12. Allyl magnesium bro-
mide (2.83 mL, 2.83 mmol, 1 M in Et2O) was added over 5 min
to the oxazolidinone 11 (540 mg, 1.41 mmol) in THF (10 mL) at
-78 ◦C. After 2.5 h, saturated NH4Cl(aq) (5 mL) was added, the
mixture was allowed to warm to room temp., and was extracted
with Et2O (3 ¥ 15 mL). The combined organic extracts were
dried (Na2SO4), filtered and evaporated. Purification by column
chromatography on silica, eluting with EtOAc–petrol (1 : 3), gave
the diene 12 (380 mg, 63%) as an oil; [a]2D2 -8.0 (0.5, CH2Cl2);
v
max/cm-1 3405, 3075, 2935, 2865, 1635, 1615; 1H NMR (250 MHz,
(S)-4-[(R)-1-(4-Methoxybenzyloxy]pent-4-en-2-yl)oxazolidin-2-
one 10. To a suspension of NaH (50 mg, 2 mmol) in Et2O
(28 ml) was added p-methoxybenzyl alcohol (2.4 mL, 20 mmol)
at room temperature. After 30 min, the mixture was cooled to
0 ◦C and Cl3CCN (2.1 mL, 20 mmol) was added. The mixture was
allowed to warm to room temperature. After 4 h, the solvent was
evaporated, then petrol (30 mL) and MeOH (1 mL) were added.
The mixture was filtered through celite and evaporated. To this
oil was added alcohol 8 (1.7 g, 9.9 mmol) in CH2Cl2 (56 mL) and
CSA (250 mg, 1 mmol) at room temperature. After 18 h, saturated
aqueous NaHCO3 (15 mL) was added, the mixture was extracted
with Et2O (3 ¥ 60 mL), and the organic layers were combined,
washed with water (100 mL), dried (MgSO4) and evaporated.
Purification by column chromatography on silica, eluting with
EtOAc–petrol (1 : 4 to 4 : 5) gave the ether 10 (2.53 g, 81%) as
an oil; [a]2D0 -2.0 (1.0, CH2Cl2); vmax/cm-1 3260, 2910, 2860, 1750,
CDCl3) d = 7.40–7.24 (m, 5H), 7.03 (d, 2H, J 8.5 Hz), 6.84 (d, 2H,
J 8.5 Hz), 6.05–5.65 (m, 2H), 5.24–4.94 (m, 4H), 4.58 (d, 1H, J
16 Hz), 4.49 (ABq, 2H, J 12 Hz), 4.16 (d, 1H, J 16 Hz), 3.79 (s, 3H),
3.74–3.61 (m, 2H), 3.53 (dd, 1H, J 9.5, 3 Hz), 3.39 (dd, 1H, J 9.5,
2.5 Hz), 3.34–3.12 (m, 3H), 2.74–2.59 (m, 1H), 2.43–2.30 (m, 1H),
2.21–2.04 (m, 1H); 13C NMR (63 MHz, CDCl3) d = 173.5, 159.4,
138.3, 136.7, 131.3, 129.1, 128.5, 128.3, 128.1, 127.9, 118.6, 116.7,
114.4, 73.4, 68.4, 64.2, 63.9, 55.4, 54.2, 39.9, 35.5, 32.6; HRMS
(ES) found 424.2486, C26H34NO4 requires (MH) 424.2488; Found:
C, 73.82; H, 7.96; N, 3.02; C26H33NO4 requires C, 73.73; H, 7.85;
N, 3.31%.
(Z)-(7R,8S)-7-Benzyloxymethyl-8-hydroxymethyl-1-(4-metho-
xybenzyl)-3,6,7,8-tetrahydro-1H-azocin-2-one 13. Grubbs cata-
lyst 2nd generation catalyst (38 mg, 0.045 mmol) in 1,2-
dichloroethane (2 mL) was added via canula to the diene 12
(380 mg, 0.90 mmol) in degassed 1,2-dichloroethane (400 mL)
at 80 ◦C under N2. After 4.5 h, an additional portion of GrubbsII
catalyst (38 mg, 0.045 mmol) in 1,2-dichloroethane (2 mL) was
added and heating was continued. After 4 h, the mixture was
cooled to room temp. and the solvent was evaporated. Purification
by column chromatography on silica gel, eluting with EtOAc–
petrol (1 : 1) + 1% v/v Et3N, gave the oxazolidinone 13 (270 mg,
58%) as an oil; [a]D22 +28.6 (0.55, CH2Cl2); vmax/cm-1 3385, 2930,
2870, 1610; 1H NMR (250 MHz, CDCl3) d = 7.45–7.22 (m, 5H),
7.14 (d, 2H, J 9 Hz), 6.71 (d, 2H, J 9 Hz), 5.70–5.55 (m, 2H),
5.14 (d, 1H, J 15 Hz), 4.51 (ABq, 2H, J 12 Hz), 4.42–4.30 (m,
1H), 4.10–3.93 (m, 1H), 3.82 (d, 1H, J 15 Hz), 3.77 (s, 3H), 3.75–
3.65 (m, 1H), 3.58–3.15 (m, 3H), 2.27–1.95 (m, 2H), 1.78–1.58 (m,
2H); 13C NMR (63 MHz, CDCl3) d = 174.3, 158.9, 137.5, 131.0,
1
1640; H NMR (250 MHz, CDCl3) d = 7.23 (d, 2H, J 8.5 Hz),
6.90 (d, 2H, J 8.5), 5.77–5.61 (m, 1H), 5.53 (br, 1H), 5.08–5.02 (m,
2H), 4.48–4.45 (m, 1H), 4.41 (br, 2H), 4.18–4.12 (dd, 1H, J 8.5,
7 Hz), 3.91–3.84 (m, 1H), 3.82 (s, 3H), 3.54 (dd, 1H, J 9.5, 4 Hz),
3.37 (dd, 1H, J 9.5, 7 Hz), 2.10–1.99 (m, 2H), 1.97–1.84 (m, 1H);
13C NMR (63 MHz, CDCl3) d = 159.6, 159.3, 134.9, 129.8, 129.4,
117.6, 113.9, 73.0, 70.1, 68.8, 55.3, 55.0, 42.6, 31.9; HRMS (ES)
found 314.1356, C16H21NO4Na requires (MNa) 314.1368.
(S)-4-[(R)-1-Benzyloxymethyl-but-3-enyl]-3-(4-methoxybenzyl)-
oxazolidin-2-one 11. The oxazolidinone 10 (1.50 g, 8.76 mmol)
in THF (15 mL) was added to a suspension of KH (30% in oil,
1.40 g, 10.5 mmol, prewashed with dry pentane under N2) in
◦
THF (30 mL) at 0 C and the mixture was heated under reflux.
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128.7, 128.5, 128.3, 128.1, 127.9, 126.6, 114.2, 73.6, 71.5, 62.4,
61.1, 55.3, 46.4, 42.1, 40.1, 26.3; HRMS (ES) found 396.2172,
C24H30NO4 requires (MH) 396.2175; Found: C, 72.60; H, 7.00; N,
3.38; C24H29NO4 requires C, 72.89; H, 7.39; N, 3.54%.
(m, 3H), 3.85–3.77 (m, 1H), 3.81 (s, 3H), 3.39 (dd, 1H, J 10, 6 Hz),
3.34 (dd, 1H, J 10, 7.5, Hz), 3.12 (ddd, 1H, J 15, 4, 3 Hz), 2.69–
2.64 (m, 1H), 2.60–2.52 (m, 1H), 2.30 (m, 2H), 2.17–2.13 (m, 1H);
13C NMR (125 MHz, CDCl3) d = 159.3, 129.8, 129.5, 129.3, 125.7,
113.8, 73.1, 70.3, 63.7, 57.4, 55.2, 43.0, 39.7, 27.6, 26.7; HRMS
(ES) found 340.1517, C18H23NO4Na requires (MH) 340.1525.
(Z)-(2S,3R)-3-Benzyloxymethyl-1-(4-methoxy-benzyl)-8-oxo-
1,2,3,4,7,8-hexahydro-azocine-2-carbaldehyde 14. Dess–Martin
periodinane (118 mg, 0.28 mmol) was adde◦d to the lactam 13
(100 mg, 0.25 mmol) in CH2Cl2 (2 mL) at 0 C. After 2 h, Et2O
(10 mL) and petrol (10 mL) were added, the mixture was filtered on
a short pad of silica (rinsing with Et2O–petrol, 1 : 1). The solvent
was evaporated to give the aldehyde 14 (60 mg, 60%) as an oil; [a]D22
-37.5 (0.56, CH2Cl2); vmax/cm-1 2960, 2920, 2850, 1725, 1655; 1H
NMR (250 MHz, CDCl3) d = 9.47 (s, 1H), 7.35–7.16 (m, 5H), 7.15
(d, 2H, J 8.5 Hz), 6.65 (d, 2H, J 8.5 Hz), 5.85–5.63 (m, 2H), 4.72
(br d, 1H, J 14 Hz), 4.48–4.42 (m, 1H), 4.38 (ABq, 2H, J 12 Hz),
4.19 (br d, 1H, J 14 Hz), 3.70 (s, 3H), 3.55—3.35 (m, 2H), 3.06
(dd, 1H, J 14, 4.5 Hz), 2.87 (dd, 1H, J 14, 5.5 Hz), 2.40–2.15 (m,
2H), 1.95–1.82 (m, 1H); 13C NMR (63 MHz, CDCl3) d = 198.8,
173.7, 159.0, 137.0, 129.8, 128.5, 127.9, 127.8, 114.0, 73.2, 71.9,
66.4, 55.3, 50.8, 43.2, 29.8, 24.8; HRMS (ES) found 416.1830,
C24H27NO4Na requires (MNa) 416.1838; m/z (ES) 416 (48%), 394
(100).
(Z)-{3-[(4-Methoxybenzyloxy)methyl]-1,2,3,4,7,8-hexahydro-
azocin-2-yl}methanol 17. NaOH (342 mg, 8.56 mmol) in ethanol
(5.2 mL) and water (1.7 mL) was added to oxazolidinone 16
(435 mg, 1.52 mmol) and the mixture was heated under reflux.
After 18 h, CH2Cl2 (10 mL) was added and the mixture was
washed with brine (3 ¥ 15 mL). The organic layer was dried
(MgSO4) and the solvent was evaporated. Purification by column
chromatography on silica, eluting with CH2Cl2–MeOH–NH3
(95 : 5 : 1), gave the amine 17 (387 mg, 95%) as an oil; [a]2D0 -8.1 (3.8,
MeOH); vmax/cm-1 3380, 3330, 3010; 1H NMR (250 MHz, CDCl3)
d = 7.25 (d, 2H, J 8.5 Hz), 6.89 (d, 2H, J 8.5 Hz), 5.85–5.64 (m,
2H), 4.42 (s, 2H), 3.81 (s, 3H), 3.52–3.38 (m, 4H), 3.10–3.01 (m,
1H), 2.89 (dt, 1H, J 7, 4 Hz), 2.61–2.47 (m, 2H), 2.30–1.87 (m, 4H);
13C NMR (63 MHz, CDCl3) d = 159.3, 130.4, 130.0, 129.8, 129.3,
113.8, 73.2, 71.1, 64.7, 59.6, 55.3, 49.3, 41.8, 30.3, 28.5; HRMS
(ES) found 292.1912, C17H26NO3 requires (MH) 292.1913.
(S)-4-[(R)-1-(4-Methoxybenzyloxy)pent-4-en-2-yl]-3-(but-3-
enyl)oxazolidin-2-one 15. NaOH (610 mg, 15 mmol), K2CO3
(620 mg, 4.5 mmol) and n-Bu4NHSO4 (70 mg, 0.2 mmol) were
added to the oxazolidinone 10 (640 mg, 2 mmol) in PhMe (11 mL).
To this mixture was added 4-bromo-1-butene (0.64 mL, 6.1 mmol)
and the mixture was heated under reflux. After 30 min, water
(15 mL) was added and the mixture was extracted with Et2O (3 ¥
40 mL). The organic layers were dried (MgSO4) and evaporated to
give the diene 15 (697 mg, 99%) as an oil; [a]2D0 7.6 (7.5, MeOH);
(Z)-tert-Butyl
xymethyl)-3,4,7,8-tetrahydroazocine-1(2H)-carboxylate
3-((4-methoxybenzyloxy)methyl)-2-(hydro-
18.
NaHCO3 (72 mg, 0.86 mmol) in water (1.25 mL) was added to
the amine 17 (249 mg, 0.86 mmol) in dioxane (2.5 mL) at room
temperature. After 10 min, further NaHCO3 was added until
the pH of the solution reached 10. To the mixture was added
di-tert-butyldicarbonate (0.2 mL, 0.86 mmol). After 18 h, water
(10 mL) was added and the mixture was extracted with CH2Cl2
(3 ¥ 10 mL). The organic layers were dried (MgSO4), evaporated
and purified by column chromatography on silica, eluting with
EtOAc-petrol (1 : 1), to give the carbamate 18 (329 mg, 98%) as an
oil; [a]2D0 2.9 (0.7, MeOH); vmax/cm-1 3430, 3010, 2920, 2860, 1690;
1H NMR (500 MHz, CDCl3) d = 7.27–7.19 (m, 2H), 6.88–6.82
(m, 2H), 5.79–5.67 (m, 2H), 4.52–4.38 (m, 2H), 4.13–3.87 (m,
4H), 3.81 (s, 3H), 3.52–3.34 (m, 2H), 2.72–2.62 (m, 1H), 2.41–2.35
(m, 1H), 2.31–1.98 (m, 4H), 1.45 (s, 9H); 13C NMR (125 MHz,
CDCl3) d = 159.1, 155.7, 130.7, 130.6, 129.3, 129.1, 113.8, 79.4,
72.7, 72.6, 63.4, 61.8, 55.3, 50.8, 43.5, 28.5, 27.2, 27.1; HRMS
(ES) found 414.2241, C22H33NO5Na requires (MNa) 414.2256.
v
max/cm-1 2910, 2860, 1740, 1640, 1610; 1H NMR (250 MHz,
CDCl3) d = 7.21 (d, 2H, J 9 Hz), 6.90 (d, 2H, J 9 Hz), 5.82–
5.67 (m, 2H), 5.14–5.04 (m, 4H), 4.42 (d, 1H, J 11.5 Hz), 4.36
(d, 1H, J 11.5 Hz), 4.2–4.14 (m, 2H), 4.09–4.05 (m, 1H), 3.82 (s,
3H), 3.59 (dt, 1H, J 14, 7.5 Hz), 3.48 (dd, 1H, J 9.5, 3.5 Hz) 3.37
(dd, 1H, J 9.5, 6 Hz), 3.06–2.95 (ddd, 1H, J 14, 7, 5.5 Hz), 2.37–
2.23 (m, 2H), 2.13–2.01 (m, 3H); 13C NMR (63 MHz, CDCl3)
d = 159.2, 158.5, 135.4, 134.6, 129.8, 129.2, 117.3, 117.2, 113.8,
72.9, 68.7, 63.8, 56.3, 55.2, 41.1, 38.4, 31.6, 28.6; HRMS (ES)
found 368.1854, C20H27NO4Na requires (MNa) 368.1838; Found:
C, 69.31; H, 7.84; N, 4.00; C20H27NO4 requires C, 69.54; H, 7.88;
N, 4.05%.
(Z)-tert-Butyl 3-[(4-methoxybenzyloxy)methyl]-2-formyl-3,4,7,
8-tetrahydroazocine-1(2H)-carboxylate 19. Dess–Martin perio-
dinane (330 mg, 0.76 mmol) was added to the alcohol 18 (259 mg,
0.66 mmol) in CH2Cl2 (3.6 mL) at 0 ◦C and the mixture was
allowed to warm to room temperature. After 4 h, NaOH (1 M,
2.6 mL) was added and the mixture was extracted with Et2O (3 ¥
10 mL). The organic layers were dried (MgSO4) and evaporated
to give the aldehyde 19 (221 mg, 86%) as an oil; [a]2D0 -22.4 (1.05,
CH2Cl2); vmax/cm-1 2930, 2860, 1735, 1685; 1H NMR (250 MHz,
CDCl3, mixture of rotamers) d = 9.58 (s, 0.5H), 9.53 (s, 0.5H), 7.27
(d, 2H, J 8.5 Hz), 6.89–6.83 (m, 2H), 5.90–5.66 (m, 2H), 4.55 (d,
0.5H, J 11.5 Hz), 4.52 (d, 0.5H, J 11.5 Hz), 4.45–4.40 (m, 0.5H),
4.39 (d, 0.5H, J 11.5 Hz), 4.32 (d, 0.5H, J 11.5 Hz), 4.19–4.10 (m,
0.5H), 3.82–3.71 (m, 1H), 3.81 (s, 3H), 3.68-3.48 (m, 1H), 3.21–
3.07 (m, 1H), 2.76–2.34 (m, 4H), 2.20–1.97 (m, 2H), 1.47 (s, 4.5H),
1.36 (s, 4.5H); 13C NMR (63 MHz, CDCl3, mixture of rotamers)
(10R,10aS,Z)-10-[(4-Methoxybenzyloxy)methyl]-5,6,10,10a-
tetrahydro-1H-oxazolo[3,4-a]azocin-3(9H)-one 16. Diene 15
(116 mg, 0.34 mmol) was added to de-gassed dry PhMe (85 mL)
at room temperature. Grubbs 2nd generation ruthenium catalyst14
(9.5 mg, 0.007 mmol, 3.3 mol%) was added at 40 ◦C. After
1 h, further catalyst (9.5 mg, 0.0073 mmol, 3.3 mol%) was
added. After a further 1 h, DMSO (0.5 mL) was added and the
mixture was allowed to cool to room temperature. After 18 h, the
solvent was evaporated, and the residue was purified by column
chromatography on silica, eluting with EtOAc–petrol (1 : 9 to 2 : 3),
to give the alkene 16 (78.6 mg, 73%) as an oil; [a]2D0 -21.1 (2.5,
CH2Cl2); vmax/cm-1 2930, 2860, 1740, 1610; 1H NMR (500 MHz,
CDCl3) d = 7.23 (d, 2H, J 9 Hz), 6.89 (d, 2H, J 9 Hz), 5.68–5.58
(m, 2H), 4.41 (d, 1H, J 11.5 Hz), 4.37 (d, 1H, J 11.5 Hz), 4.23–4.13
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d = 199.4, 198.5, 159.2, 159.0, 155.8, 154.7, 131.0, 130.8, 130.6,
130.4, 130.2, 129.6, 129.3, 129.1, 113.8, 113.6, 82.2, 80.6, 72.6,
72.4, 71.3, 70.9, 68.2, 67.9, 55.2, 49.7, 49.4, 42.3, 41.5, 28.3, 28.1,
27.8, 27.6, 27.4, 27.3; HRMS (ES) found 412.2113, C22H31NO5Na
requires (MNa) 412.2100.
Evidence that this product was a mixture of rotamers, rather
than diastereomers, was obtained in two ways: firstly, reduction
(DIBAL-H) gave the alcohol 18, which was a single diastereomer
by NMR spectroscopy; secondly, treatment of 19 with DBU gave
recovered 19 together with a new aldehyde with two (rotameric)
singlets in the 1H NMR spectrum for the aldehyde CH at d = 9.70
and 9.63.
(1.8, CH2Cl2); vmax/cm-1 2950, 1680; 1H NMR (500 MHz, CDCl3,
mixture of rotamers) d = 7.38–7.29 (m, 5H), 4.56–4.48 (m, 2.5H),
4.41–4.39 (m, 1H), 4.24–4.23 (m, 0.5H), 3.83–3.73 (m, 1H), 3.70–
3.65 (m, 0.5H), 3.55–3.37 (m, 3.5H), 3.21–3.14 (m, 1H), 2.72 (s,
1.5H), 2.71 (s, 1.5H), 2.36 (m, 1H), 1.99-1.86 (m, 1H), 1.76–1.66
(m, 3H), 1.48 (s, 4.5H), 1.43 (s, 4.5H); 13C NMR (125 MHz, CDCl3,
mixture of rotamers) d = 156.2, 155.8, 138.5, 138.3, 128.5, 128.4,
127.7, 127.6, 127.5, 79.4, 79.3, 77.7, 77.3, 74.2, 73.9, 73.8, 73.3,
73.2, 73.1, 59.8, 59.3, 49.4, 49.2, 48.7, 48.6, 47.6, 47.1, 39.6, 38.5,
29.1, 28.8, 28.6, 28.5, 25.6, 25.3; HRMS (ES) found 388.2373,
C22H32N2O4 requires (M) 388.2362.
Amide product 23. TFA (3 mL, 0.4 mmol) was added to the
cycloadduct 22a (127 mg, 0.33 mmol) in CH2Cl2 (9 mL) at room
temperature. After 45 min, the solvent was evaporated, toluene
(20 mL) was added and the solvent was evaporated. Purification by
column chromatography on silica, eluting with CH2Cl2–MeOH–
NH3 (9.7 : 0.3 : 0.1), gave the secondary amine (80 mg, 84%) as
Intermolecular cycloadducts 20. Sarcosine (36 mg, 0.4 mmol)
and N-methylmaleimide (46 mg, 0.4 mmol) were added to the
aldehyde 19 (73 mg, 0.19 mmol) in DMF (1 mL) and the mixture
was heated at 120 ◦C. After 18 h, the mixture was cooled and
was filtered through silica (rinsing with EtOAc). The solvent
1
1
an oil; [a]2D2 3.9 (2.5, CH2Cl2); vmax/cm-1 3410, 2950; H NMR
was evaporated to give the cycloadducts 20 as an oil; H NMR
(500 MHz, CDCl3, mixture of 4 diastereoisomers) d = 7.30–7.20
(m, 8H), 6.90–6.84 (m, 8H), 5.82–5.66 (m, 8H), 4.52–4.37 (m, 8H),
4.22–4.10 (m, 4H), 3.85–3.79 (m, 8H), 3.81–3.79 (m, 12H), 3.67–
3.03 (m, 28H), 2.95–2.89 (m, 12H), 2.67–2.30 (m, 4H), 2.34–2.27
(m, 12H), 2.20–1.95 (m, 16H), 1.48–1.45 (m, 36H); HRMS (ES)
found 528.3054, C29H42N3O6 requires (MH) 528.3074.
(500 MHz, C6D6) d = 8.50 (br, 1H), 7.38–7.21 (m, 5H), 4.44 (d, 1H,
J 12 Hz), 4.31 (d, 1H, J 12 Hz), 3.91 (d, 1H, J 7.5 Hz), 3.86 (dt, 1H,
J 11, 2 Hz), 3.57 (ddd, 1H, J 14, 9.5. 6 Hz), 3.45 (dd, 1H, J 9, 5 Hz),
3.35 (t, 1H, J 7.5 Hz), 3.23 (dd, 1H, J 9, 5 Hz), 3.17 (dt, 1H, J 14,
6 Hz), 2.87–2.84 (m, 1H), 2.68–2.64 (m, 1H), 2.62 (s, 3H), 1.55–1.32
(m, 4H);13C NMR (125 MHz, C6D6) d = 138.7, 128.3, 128.0, 127.8,
76.2, 73.2, 72.4, 72.3, 60.6, 49.9, 47.2, 42.5, 38.2, 26.6, 25.4; HRMS
(ES) found 289.1915, C17H25N2O2 requires (MH) 289.1916. To this
amine (60 mg, 0.21 mmol) in CH2Cl2 (1 mL) was added DMAP
(13 mg, 0.11 mmol), 4-bromobenzoyl chloride (0.12 g, 0.53 mmol)
and triethylamine (0.088 mL, 0.63 mmol) at room temperature.
After 2.5 h, NaHCO3 (10 mL) was added and the mixture was
extracted with Et2O (3 ¥ 15 mL). The organic layers were dried
(MgSO4) and the solvent was evaporated to give the amide 23
(67 mg, 48%) as ne◦edles, which was recrystallized from EtOAc–
Et2O; m.p. 242–246 C; 1H NMR (500 MHz, CDCl3, rotamers) d =
8.42–8.33 (s, 1H), 7.69–7.56 (m, 4H), 7.40–7.22 (m, 7H), 7.13–7.06
(m, 2H), 4.61–4.15 (m, 4H), 3.89–3.44 (m, 2H), 3.21–3.16 (m, 1H),
3.05–3.00 (m, 1H), 2.90–2.55 (m, 1H), 2.49–2.41 (m, 1H), 2.16–
2.04 (m, 2H), 1.65–1.55 (m, 1H), 1.31–1.19 (m, 2H), 0.90–0.82
(m, 1H); HRMS (ES) found 641.0679, C30H31N2O479Br2 requires
(MH) 641.0651; m/z (ES) 645 (50%), 643 (100), 641 (50).
(2S,3R,Z)-tert-Butyl
tetrahydroazocine-1(2H)-carboxylate
3-(benzyloxymethyl)-2-formyl-3,4,7,8-
21. Dess–Martin
periodinane (254 mg, 0.6 mmol) was added to the alcohol
(OBn equivalent of OPMB compound 18 – for its preparation
and characterization, see ESI†) (189 mg, 0.53 mmol) in CH2Cl2
◦
(1.5 mL) at 0 C and the mixture was allowed to warm to room
temperature. After 4 h, NaOH (1 M, 2.0 mL) was added and the
mixture was extracted with Et2O (3 ¥ 10 mL). The organic layers
were dried (MgSO4) and evaporated and the residue was purified
by column chromatography on silica, eluting with EtOAc–petrol
(15 : 85), to give the aldehyde 21 (131 mg, 70%) as an oil; [a]D20
1
-10.7 (2.1, CH2Cl2); vmax/cm-1 2930, 1730, 1710, 1680; H NMR
(500 MHz, CDCl3, mixture of rotamers) d = 9.53 (s, 0.5H), 9.78 (s,
0.5H), 7.28–7.19 (m, 5H), 5.83–5.65 (m, 2H), 4.57–4.52 (m, 1H),
4.43–4.34 (m, 1.5H), 4.11–4.07 (m, 0.5H), 3.78–3.76 (m, 0.5H),
3.67–3.65 (m, 0.5H), 3.63–3.62 (m, 0.5H), 3.45–3.44 (m, 0.5H),
3.16 (t, 0.5H, J 10 Hz), 3.09 (t, 0.5H, J 10 Hz), 2.67–2.37 (m,
4H), 2.14–1.97 (m, 2H), 1.37 (s, 4.5H), 1.25 (s, 4.5H); 13C NMR
(100 MHz, CDCl3, mixture of rotamers) d = 199.5, 198.6, 155.9,
154.8, 138.9, 138.5, 130.9, 130.4, 130.3, 129.6, 128.4, 128.3, 127.7,
127.6, 127.6, 127.4, 82.3, 80.7, 73.1, 72.8, 71.6, 71.2, 68.3, 68.0,
49.8, 49.4, 42.3, 41.5, 28.3, 28.2, 27.8, 27.6, 27.5, 27.4; HRMS
(ES) found 360.2184, C21H30NO4 requires (MH) 360.2175; m/z
(ES) 384 (100%); 382 (95), 360 (20), 304 (100).
Acknowledgements
We thank the EPSRC and the University of Sheffield, UK for
support of this work. Adam J. M. Burrell and Samaresh Jana are
thanked for carrying out some alternative related studies.
Notes and references
Cycloadduct 22a. NaHCO3 (102 mg, 1.22 mmol) was
added to the aldehyde 21 (97 mg, 0.27 mmol), and N-
methylhydroxylamine·HCl (69 mg, 0.81 mmol) in EtOH (2.8 mL)
and the mixture was heated in a sealed tube at 125 ◦C. After
4 h, the solvent was evaporated, H2O (10 mL) was added and the
mixture was extracted with EtOAc (3 ¥ 8 mL). The organic layers
were dried (MgSO4) and the solvent was evaporated. Purification
by column chromatography on silica, eluting with EtOAc–petrol
(1 : 4), gave the cycloadduct 22a (76 mg, 72%) as an oil; [a]2D0 4.7
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