Synthetic studies towards the core structure of nakadomarin a by a thioamide-based strategy

Article abstract of DOI:10.1002/ejoc.201301063

The tricyclic BCD substructure of the marine natural product nakadomarin A has been synthesised. The strategy utilised a key carbon-carbon bond-forming reaction between a furan and an N-acyliminium ion derived from a secondary thiolactam. In addition, a novel three-component coupling reaction between a thioamide, an allylic bromide and an isocyanate, leading to the establishment of two new stereogenic centres, is reported. Two key steps in a projected total synthesis of nakadomarin A have been realised by using the unique chemistry of thioamides. Formation of the carbocyclic B ring can be effected by nucleophilic attack of a furan on a thiolactam-derived iminium ion, and the key quaternary centre can be established by a novel three-component coupling reaction.

Full text of DOI:10.1002/ejoc.201301063

FULL PAPER
DOI: 10.1002/ejoc.201301063
Synthetic Studies Towards the Core Structure of Nakadomarin A by a
Thioamide-Based Strategy
Jai K. Chavda,[a] Panayiotis A. Procopiou,[b] Peter N. Horton,[c] Simon J. Coles,[c] and
Michael J. Porter*[a]
Keywords: Natural products / Alkaloids / Sigmatropic rearrangement / Multicomponent reactions
The tricyclic BCD substructure of the marine natural product
nakadomarin A has been synthesised. The strategy utilised a
key carbon–carbon bond-forming reaction between a furan
and an N-acyliminium ion derived from a secondary thiolact-
am. In addition, a novel three-component coupling reaction
between a thioamide, an allylic bromide and an isocyanate,
leading to the establishment of two new stereogenic centres,
is reported.
idine A ring through hydroboration of an alkene such as 3
and subsequent functionalisation. It was anticipated that
formation of the cyclopentanoid B ring would be possible
through cyclisation of the furan in 4 onto an electrophile
derived from the thiolactam portion of the molecule with
Introduction
Nakadomarin A (1),
a hexacyclic alkaloid of the
manzamine family, was isolated in 1997 by Kobayashi et al.
from the marine sponge Amphimedon sp., collected off the
Kerama Islands in Japan.[1] It displays cytotoxicity against
L1210 murine lymphoma cells, is an inhibitor of cyclin-de-
pendent kinase 4 and shows antifungal and antibacterial
activity.
The structure of nakadomarin A incorporates a tetracy-
clic furan-containing core (the ABCD ring system) fused to
an eight-membered E ring and bridged by a fifteen-mem-
bered F ring. The combination of intriguing structural fea-
tures and promising biological activity has made the com-
pound a popular target for synthesis. Several total syntheses
have been published,[2] as have numerous reports on the
synthesis of various substructures.[3–9]
Our initial retrosynthetic analysis of nakadomarin A is
depicted in Scheme 1. Late-stage construction of the E and
F rings by ring-closing metathesis would lead back to the
tetracyclic substructure 2. We planned to install the piper-
[a] Department of Chemistry, University College London,
Christopher Ingold Building,
20 Gordon Street, London, WC1H 0AJ, UK
E-mail: m.j.porter@ucl.ac.uk
http://www.ucl.ac.uk/chemistry/staff/academic_pages/
michael_porter
[b] GlaxoSmithKline Research & Development Limited, Medicines
Research Centre,
Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
[c] UK National Crystallography Service, School of Chemistry,
University of Southampton,
Southampton, SO17 1BJ, UK
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301063.
© 2013 The Authors. Published by Wiley-VCH Verlag GmbH &
Co. KGaA. This is an open access article under the terms of
the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the
original work is properly cited.
Scheme 1. Retrosynthesis of nakadomarin A (1).
Eur. J. Org. Chem. 2014, 129–139
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129

M. J. Porter et al.
FULL PAPER
subsequent reductive removal of the sulfur. Padwa and co- being the 1,3,5,2-oxathiazaphosphepane 14, in which a P–S
workers have shown that mono-N-substituted thioamides, unit has been inserted into the benzylic C–O bond. Clivio
on treatment with α-bromoacyl chlorides, are transformed and co-workers[16] previously reported the insertion of
through N-acylation and S-alkylation into potent N-acyl- Lawesson’s reagent into the C–O bond of a dihydrouracil
iminium ion electrophiles, which react intramolecularly nucleoside and found that the unwanted ArPS2 unit was
with nucleophilic alkenes, indoles and benzenes.[10]
expelled upon extended heating. In our case, however, fur-
We planned to establish the vicinal stereocentres of com- ther heating of 14 in pyridine led only to recovery of the
pound 4 through thia-Claisen rearrangement of a diene starting material and so a revised strategy was adopted in
such as 5; reaction on the exo face of the bicyclic system, which thionation took place at a later stage.
through the chair conformation shown, should lead to the
desired stereoisomer 4. We expected that 5 would be access-
ible from the pyroglutamate-derived thiolactam 6 and (Z)-
allylic bromide 7.[11]
In this paper, we describe our model studies in two areas
of this retrosynthesis: the cyclisation of a thiolactam-de-
rived iminium ion to generate the BCD ring system of nak-
adomarin, and the development of a thia-Claisen re-
arrangement strategy to establish the stereogenic centres in
a compound related to 4.
Results and Discussion
We first focused on generating the carbocyclic B ring of
nakadomarin A in a simple model of the BCD ring system
(Scheme 2). N-Benzylpyrrolidin-2-one (8) was alkylated se-
quentially with iodomethane and 3-(bromomethyl)furan
(9), prepared as a solution in diethyl ether,[12] to afford lac-
Scheme 3. Synthesis of thiolactam 16.
tam 10. Removal of the benzyl group was effected with lith-
ium in liquid ammonia, and thionation with Lawesson’s
C-Ethoxycarbonylation of 13 was carried out according
reagent[13] then gave thiolactam 11. Treatment of this com-
pound with bromoacetyl chloride[10] in toluene at 100 °C
led to the desired tetracycle 12 in 53% yield. The same
transformation could be effected in higher yield (73%) by
treatment of thiolactam 11 with methyl bromoacetate in tol-
uene at reflux.
to a literature procedure.[17] Subsequent alkylation with 3-
(bromomethyl)furan (9) afforded 15 as a 5:1 diastereomeric
mixture; the major diastereomer depicted was isolated in
41% yield. Hydrolysis of the benzylidene group of 15 with
p-toluenesulfonic acid was followed by acetylation of the
resulting alcohol and thionation to give secondary thiolact-
am 16.
Two α-bromocarbonyl electrophiles 17 and 18, each con-
taining a further carbon chain for elaboration of the E ring,
were prepared for reaction with 16 (Scheme 4). Lactone 17
was synthesised by conversion of δ-valerolactone into the
corresponding TMS ketene acetal and treatment with
bromine, and acyl chloride 18 was synthesised by double
deprotonation of hex-5-enoic acid with LDA, bromination
with carbon tetrabromide and then conversion of the re-
sulting α-bromo acid into an acid chloride using oxalyl
chloride.
Initial attempts to effect direct reaction of thiolactam 16
with lactone 17 resulted in recovery of the starting materi-
als, and so the nucleophilicity of 16 was increased through
deprotonation. Treatment of 16 with sodium hydride fol-
Scheme 2. Synthesis of the BCD ring system (12).
Our next aim was to extend this study through the prepa- lowed by reaction with α-bromo-δ-valerolactone (17) af-
ration of a compound with functionalities that would allow forded thioimidate 19 as a mixture of diastereoisomers
the construction of the eight-membered E ring of nakadom- (Scheme 4). On heating in toluene in a sealed tube, no acyl-
arin A. To this end, l-pyroglutaminol[14] was protected as ation of the nitrogen atom was observed; rather the sub-
its benzylidene N,O-acetal 13 (Scheme 3).[15] Attempts to strate underwent an Eschenmoser sulfide contraction to
convert 13 into its thiolactam analogue using Lawesson’s give vinylogous carbamate 20 as a single unassigned geo-
reagent were unsuccessful, with the only product isolated metric isomer. Given the lack of base or thiophile in the
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Synthetic Studies Towards the Core Structure of Nakadomarin A
Scheme 5. Formation of bicycle 22.
mixture of diastereomers. Attempts to thionate this com-
pound to give 26 by using either Lawesson’s reagent or
phosphorus pentasulfide were unsuccessful.
Scheme 4. Reactions of thiolactam 16.
reaction medium, the observation of this product is some-
what surprising.
Reaction of thiolactam 16 with the unsaturated α-
bromoacyl chloride 18 in toluene gave two major products.
The desired product 21 was obtained in 21% yield as an
inconsequential 4:1 mixture of diastereomers. The major
product, however, was the diene 22, which was isolated as
a single, but unidentified diastereoisomer. This unexpected
product may be formed as shown in Scheme 5. Reaction of
thiolactam 16 with acid chloride 18 through S-alkylation
and N-acylation gives the expected N-acyliminium ion 23,
which can either react with the nucleophilic furan to pro-
duce the desired product 21, or can undergo enolisation to
give the aromatic thiazolium ion 24. If ketonisation then
occurs through addition of a proton at the carbon between
the nitrogen and sulfur atoms, cation 25 results; this can
lose a proton to give the diene 22. All attempts to improve
the yield of tetracycle 21 at the expense of the diene product
Scheme 6. Attempted synthesis of thiolactam 26.
A reversal of the step order was attempted. Acetonide
22, through modification of the reaction conditions, were 27 could be thionated, albeit in low yield, with Lawesson’s
unsuccessful. reagent, whereas the use of other thionating reagents failed;
We next investigated the thia-Claisen step of Scheme 1, decomposition was observed when 2,4-bis(phenylthio)-1,3-
and initially targeted tertiary thiolactam 26 (Scheme 6). l- dithia-2,4-diphosphetane-2,4-disulfide (Yokoyama’s rea-
Pyroglutaminol was protected as its acetonide 27 by using gent)[19] was employed, and the use of Bergman’s P4S10–
2,2-dimethoxypropane and 4-toluenesulfonic acid,[18] and pyridine complex[20] led to recovery of the starting material.
this was acylated with diethyl carbonate[2g] to give 28 as a A slightly more efficient synthesis of 29 could be achieved
Eur. J. Org. Chem. 2014, 129–139
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M. J. Porter et al.
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by starting from ethyl l-pyroglutamate (30)[21] by thion-
The reaction of thiolactam 29 with an allylic bromide
ation with Lawesson’s reagent in 82% yield,[22] followed by should give N,S-ketene acetal 31. Such compounds are
the selective reduction of the ester with lithium borohydride known to readily undergo substitution reactions with elec-
and protection using 2,2-dimethoxypropane. However, we trophiles such as acid chlorides[23] or isocyanates[24] at the
were unable to conduct a successful α-acylation of thio- nucleophilic carbon atom; our hope was that we could in-
lactam 29.
tercept the N,S-ketene acetal 31 with such an electrophile
Having failed in attempts to prepare the desired thia- to generate 32, which would then undergo the desired [3,3]-
Claisen substrate 26, we instead conceived a three-compo- sigmatropic rearrangement to give the product 33. An obvi-
nent coupling approach that would allow the stereospecific ous potential pitfall of this chemistry is that the 1,5-diene
formation of two new C–C bonds at the α position of thio- moiety of 31 may undergo the sigmatropic rearrangement
lactam 29 in a single laboratory operation. This strategy is more rapidly than it reacts with the electrophile; if this were
illustrated in Scheme 7.
the case, the simple thia-Claisen product 34 would be ob-
tained.
Initial studies on the three-component coupling reaction
were carried out by using (E)-cinnamyl bromide as the all-
ylic bromide component. Deprotonation of 29 with either
n-butyllithium or lithium hexamethyldisilazide (LHMDS)
at low temperature was followed by treatment with (E)-cin-
namyl bromide. Once alkylation of the sulfur was complete,
as judged by TLC, the second electrophile was added and
the reaction mixture warmed to room temperature
(Scheme 8).
Scheme 8. Attempted three-component coupling reaction using
(E)-cinnamyl bromide.
A wide range of electrophiles were tested: ethyl chloro-
formate, acetic formic anhydride, phenyl isocyanate, chloro-
sulfonyl isocyanate, trichloroacetyl isocyanate and phos-
gene. However, under none of the conditions tried could
any of the putative three-component coupling products 35
be obtained; rather, the only compound isolated was the
product 36 from rearrangement of the first-formed N,S-
ketene acetal. This clearly indicated that the rate of acyl-
Scheme 7. Proposed three-component coupling to give 33.
Figure 1. X-ray crystal structure of 36.
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Synthetic Studies Towards the Core Structure of Nakadomarin A
passage through a column of activated alumina under nitrogen.
All reactions in anhydrous solvents were carried out in flame-dried
glassware under argon.
ation of the N,S-ketene acetal was not competitive with the
rate of sigmatropic rearrangement.
A control experiment carried out in the absence of the
second electrophile showed that the [3,3]-sigmatropic re-
arrangement to form 36 was indeed rapid, proceeding in
1-Benzyl-3-(furan-3-ylmethyl)-3-methylpyrrolidin-2-one (10):
A
stirred solution of 1-benzylpyrrolidin-2-one (8; 1.80 mL,
less than 5 min at room temperature. Under these condi- 11.4 mmol) in THF (33 mL) at –78 °C was treated dropwise with
n-butyllithium (2.5 m in hexanes, 5.50 mL, 13.7 mmol) and stirred
for 30 min. The reaction mixture was treated dropwise with MeI
(1.40 mL, 22.8 mmol) and stirred for 30 min. The reaction mixture
was warmed to room temp. and stirred for 1.5 h and then quenched
with saturated aq. NH4Cl (30 mL). The organic material was ex-
tracted with EtOAc (3ϫ 30 mL) and the combined organic extracts
were washed with H2O (30 mL) and brine (30 mL), dried (MgSO4)
and then concentrated in vacuo. Purification by flash chromatog-
raphy (SiO2, 50% EtOAc in petroleum ether) gave 1-benzyl-3-meth-
tions, 36 could be isolated in 73% yield as a 25:1 mixture
of diastereoisomers. The stereochemistry of the major iso-
mer was confirmed by X-ray crystallography (Fig-
ure 1).[25,26]
Rawal and co-workers previously reported that N,S-
ketene acetals derived from (Z)-allylic bromides rearrange
much more slowly than those derived from the correspond-
ing E isomers (3 h at reflux in THF vs. warming from
–78 °C to room temperature).[27] In light of this observa-
ylpyrrolidin-2-one (8a; 1.56 g, 72%) as a yellow oil. IR (film): ν
˜
max
tion, and given the requirement for a (Z)-allylic bromide in = 2965, 2930, 2872, 1677 cm–1. H NMR (600 MHz, CDCl3): δ =
1
3
2
3
1.24 (d, JH,H = 7.2 Hz, 3 H, CH3), 1.59 (dq, JH,H = 12.7, JH,H
the projected total synthesis (Scheme 1), we next investi-
gated the use of (Z)-cinnamyl bromide.
Fortunately, deprotonation of thiolactam 29 at 0 °C fol-
lowed by reaction with (Z)-cinnamyl bromide and then
phenyl isocyanate afforded the desired three-component
coupling product 37 in 46% yield (Scheme 9).
2
3
= 8.4 Hz, 1 H, 4-H), 2.21 (dddd, JH,H = 12.6, JH,H = 8.6, 6.7,
4.1 Hz, 1 H, 4-H), 2.52 (ddt, JH,H = 15.8, 8.7, 7.2 Hz, 1 H, 3-H),
3
2
3.15–3.19 (m, 2 H, 5-H), 4.43 (d, JH,H = 14.7 Hz, 1 H, PhCH2),
2
4.47 (d, JH,H = 14.7 Hz, 1 H, PhCH2), 7.20–7.36 (m, 5 H, Ar-
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 16.6 (CH3), 27.2 (C-
4), 36.9 (C-3), 44.8 (C-5), 46.9 (PhCH2), 127.6 (CH), 128.2 (CH),
128.8 (CH), 136.8 (C), 177.5 (C-2) ppm. MS (EI): m/z (%) = 189
(63) [M]+, 92. HRMS (EI): calcd. for C12H15NO [M]+ 189.1148;
found 189.1152.
A stirred solution of lactam 8a (1.56 g, 8.23 mmol) in THF (28 mL)
at –78 °C was treated dropwise with n-butyllithium (2.5 m in hex-
anes, 3.5 mL, 8.6 mmol) and stirred for 40 min. The reaction mix-
ture was treated with a solution of bromide 9 (prepared from
6.43 mmol of furan-3-methanol and PBr3),[12] stirred for 30 min,
and then warmed to room temp. The reaction mixture was
quenched with saturated aq. NH4Cl (20 mL) and the organic mate-
rial extracted with EtOAc (3ϫ 20 mL). The combined organic ex-
tracts were washed with H2O (20 mL) and brine (20 mL), dried
(MgSO4) and then concentrated in vacuo. Purification by flash
chromatography (SiO2, 25% EtOAc in petroleum ether) gave lac-
tam 10 (480 mg, 28% over two steps from furan-3-methanol) as a
Scheme 9. Three-component coupling reaction using (Z)-cinnamyl
bromide.
Further investigations into this three-component cou-
pling reaction and its application to the total synthesis of
nakadomarin A are ongoing.
colourless oil. IR (CH2Cl2 cast): ν
= 2961, 2930, 2871,
˜
max
1682 cm–1. H NMR (600 MHz, CDCl3): δ = 1.21 (s, 3 H, CH3),
1
2
3
1.68 (ddd, JH,H = 12.8, JH,H = 8.3, 4.5 Hz, 1 H, 4-H), 1.99 (ddd,
2JH,H = 12.8, JH,H = 9.0, 6.4 Hz, 1 H, 4-H), 2.50 (d, JH,H
=
3
2
Conclusions
2
14.1 Hz, 1 H, FurCH2), 2.80 (d, JH,H = 14.1 Hz, 1 H, FurCH2),
2
3
We have demonstrated the feasibility of two key steps in
a projected total synthesis of nakadomarin A. First, we
have shown that the carbocyclic B ring in a tricyclic ABC
substructure can be constructed by electrophilic substitu-
tion of a furan by using a thiolactam-derived acyliminium
electrophile. Secondly, we have developed a novel three-
component coupling reaction involving a thioamide, allylic
bromide and isocyanate to stereoselectively install two vici-
nal stereogenic centres, one of them quaternary.
2.86 (ddd, JH,H = 9.6, JH,H = 9.0, 4.5 Hz, 1 H, 5-H), 3.06 (ddd,
2JH,H = 9.7, JH,H = 8.4, 6.4 Hz, 1 H, 5-H), 4.36 (d, JH,H
=
3
2
14.7 Hz, 1 H, PhCH2), 4.43 (d, 2JH,H = 14.7 Hz, 1 H, PhCH2), 6.26
4
(d, JH,H = 1.3 Hz, 1 H, Fur-H), 7.11–7.33 (m, 7 H, Ar-H) ppm.
13C NMR (150 MHz, CDCl3): δ = 24.0 (CH3), 30.2 (C-4), 33.2
(Fur-CH2), 43.4 (C-2), 45.1 (C-5), 46.9 (PhCH2), 112.3 (Fur-C-4),
120.7 (Fur-C-3), 127.6 (Ph-C-1), 128.1 (CH), 128.7 (CH), 136.6
(CH), 140.8 (Fur-C-5), 142.7 (Fur-C-2), 178.5 (C-2) ppm. MS (EI):
m/z (%) = 269 (31) [M]+, 254 (13) [M – CH3]+, 187 (100) [M –
CH2Fur]+, 158 (20), 91 (69) [PhCH2]+. HRMS (EI): calcd. for
C17H19NO2 [M]+ 269.1410; found 269.1407.
3-(Furan-3-ylmethyl)-3-methylpyrrolidine-2-thione (11): A solution
of lactam 10 (373 mg, 1.38 mmol) in THF (15 mL) was added to
liquid NH3 (ca. 15 mL) at –78 °C. The stirred solution was treated
with Na (65 mg, 2.8 mmol) and stirred for 10 min. The reaction
mixture was quenched with satd. aq. NH4Cl (15 mL) and then
warmed to room temp. overnight. The solvent was removed in
vacuo and the organic material extracted with EtOAc (3ϫ 30 mL).
Experimental Section
General: (Bromomethyl)furan (9),[12] lactam 13,[15] Lawesson’s rea-
gent [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-di-
sulfide][28] and hex-5-enoic acid[29] were prepared by literature pro-
cedures. All other reagents were used as obtained from commercial
sources. Solvents (THF, toluene, dichloromethane) were dried by
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M. J. Porter et al.
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The combined organic extracts were washed with H2O (30 mL) and
brine (30 mL), dried (MgSO4) and then concentrated in vacuo to
give 3-(furan-3-ylmethyl)-3-methylpyrrolidin-2-one (10a; 234 mg,
at reflux for 6 h and then concentrated in vacuo. Purification by
flash chromatography (SiO2, 50% EtOAc in petroleum ether) gave
thiolactam 14 (340 mg, 79 %) as a colourless solid, m.p. 138–
95%) as a pale-yellow oil. IR (CDCl3 cast): ν
= 3230, 2964,
139 °C; [α]2D0 = –74 (c = 1.0, CHCl ). IR (solid): νmax = 2924, 2838,
˜
˜
max
3
2927, 2872, 1692 cm–1. H NMR (600 MHz, CDCl3): δ = 1.17 (s,
1591 cm–1. H NMR (600 MHz, CDCl3): δ = 2.02 (m, 1 H, 10-H),
1
1
2
3
2
3
3 H, CH3), 1.78 (ddd, JH,H = 12.7, JH,H = 8.0, 4.5 Hz, 1 H, 4-
2.40 (m, 1 H, 10-H), 3.12 (ddd, JH,H = 18.1, JH,H = 8.7, 2.6 Hz,
1 H, 9-H), 3.21 (ddd, JH,H = 17.3, JH,H = 10.5, 7.9 Hz, 1 H, 9-
2
3
2
3
H), 2.09 (ddd, JH,H = 12.7, JH,H = 8.6, 6.6 Hz, 1 H, 4-H), 2.48
2
2
3
2
(d, JH,H = 14.2 Hz, 1 H, FurCH2), 2.71 (d, JH,H = 14.2 Hz, 1 H,
H), 3.89 (s, 3 H, OCH3), 4.04 (ddd, JH,P = 28.2, JH,H = 12.4,
FurCH2), 3.04 (td, 2JH,H = 9.0, 3JH,H = 9.0, 4.5 Hz, 1 H, 5-H), 3.22
3JH,H = 5.7 Hz, 1 H, 2-H), 4.94 (m, 1 H, 1-H), 5.09 (ddd, JH,P
=
3
2
2
3
(br. q, JH,H
=
3JH,H = 8.0 Hz, 1 H, 5-H), 6.28 (s, 1 H, Fur-H),
15.2, JH,H = 12.1, JH,H = 6.2 Hz, 1 H, 2-H), 6.99–7.07 (m, 3 H,
6.79 (br. s, 1 H, NH), 7.24 (s, 1 H, Fur-H), 7.32 (s, 1 H, Fur-
6-H, Ar-H), 7.28–7.39 (m, 5 H, Ar-H), 7.93 (dd, 3JH,P = 14.4, 3JH,H
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 23.5 (CH3), 32.7 (C- = 8.8 Hz, 2 H, Ar-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 28.0
4), 32.8 (Fur-CH2), 39.0 (C-3), 44.0 (C-5), 112.2 (Fur-C-4), 120.7
(Fur-C-3), 140.7 (Fur-C-5), 142.8 (Fur-C-2), 182.8 (C-2) ppm. MS
(C-10), 43.7 (C-9), 55.7 (OCH3), 62.5 (C-1), 64.8 (d, 3JC,P = 4.2 Hz,
3
2
C-6), 65.6 (d, JC,P = 6.6 Hz, C-2), 114.5 (d, JC,P = 16.1 Hz,
(EI): m/z (%) = 179 (41) [M]+, 164 (35) [M – CH3]+, 98 (35), 82 CHCP), 124.7 (d, 1JC,P = 129.9 Hz, CP), 127.3 (CH), 129.11 (CH),
(100) [FurCH2]+. HRMS (EI): calcd. for C10H13NO2 [M]+ 129.15 (CH), 133.5 (d, JC,P = 14.3 Hz, CHCHCP), 135.4 (d, JC,P
3
3
4
179.0941; found 179.0944.
= 6.6 Hz, Ph-C-1), 163.6 (d, JC,P = 3.6 Hz, MeOC), 203.3 (C-
8) ppm. MS (CI): m/z (%) = 422 (44) [MH]+, 300 (100) [MH –
SCHPh]+. HRMS (CI): calcd. for C20H22NO2PS3 [MH]+ 422.0472;
found 422.0474.
A stirred solution of lactam 10a (234 mg, 1.31 mmol) in THF
(5 mL) was treated with Lawesson’s reagent (292 mg, 0.721 mmol).
The reaction mixture was heated at 60 °C for 2 h and then concen-
trated in vacuo. Purification by flash chromatography (SiO2, 25%
EtOAc in petroleum ether) gave thiolactam 11 (204 mg, 80%) as
Ethyl (2R,5S,7R)-7-(Furan-3-ylmethyl)-8-oxo-2-phenyl-3-oxa-1-aza-
bicyclo[3.3.0]octane-7-carboxylate (epi-15) and Ethyl (2R,5S,7S)-7-
(Furan-3-ylmethyl)-8-oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane-
7-carboxylate (15): Compound 13 was acylated following the pro-
cedure of Moloney and co-workers.[17b] A flask containing a stirred
solution of lactam 13 (8.7 g, 43 mmol) and diethyl carbonate
(21 mL, 170 mmol) in toluene (70 mL) was fitted with a Dean–
Stark trap. The solution was heated at reflux for 4.5 h, cooled to
0 °C and then added to a pre-washed NaH (60% dispersion in min-
eral oil, 4.12 g, 100 mmol). The reaction mixture was heated at re-
flux for 14 h and then cooled to 0 °C. It was then treated with
AcOH (4.40 g, 73.3 mmol) and stirred for 1 h at room temp. The
mixture was filtered and the filtrate concentrated in vacuo. Purifi-
cation by flash chromatography (SiO2, 30–50% EtOAc in petro-
leum ether, gradient elution) gave ethyl (2R,5S,7RS)-8-oxo-2-
phenyl-3-oxa-1-azabicyclo[3.3.0]octane-7-carboxylate (13a) as a
13:1 mixture of diastereoisomers (7.3 g, 62%) as a yellow solid,
m.p. 66–67 °C (ref.[17b] 85–87 °C for a 1:1 ratio of diastereoiso-
an orange oil. IR (CH Cl cast): νmax = 3166 (br), 2967, 2926, 2888,
˜
2
2
1524 cm–1. H NMR (600 MHz, CDCl3): δ = 1.30 (s, 3 H, CH3),
1
2
3
1.95 (ddd, JH,H = 12.8, JH,H = 8.6, 5.7 Hz, 1 H, 4-H), 2.23 (ddd,
2JH,H = 12.8, JH,H = 8.7, 5.8 Hz, 1 H, 4-H), 2.67 (d, JH,H
=
3
2
2
14.3 Hz, 1 H, Fur-CH2), 2.88 (d, JH,H = 14.3 Hz, 1 H, Fur-CH2),
3.16 (dddd, JH,H = 11.0, JH,H = 8.7, 5.7, 1.1 Hz, 1 H, 5-H), 3.40
(dddd, JH,H = 11.0, JH,H = 8.6, 5.9, 1.1 Hz, 1 H, 5-H), 6.37 (br.
s, 1 H, Fur-H), 7.31 (m, 1 H, Fur-H), 7.33 (t, JH,H
2
3
2
3
= =
4JH,H
3
1.7 Hz, 1 H, Fur-H), 7.67 (br. s, 1 H, NH) ppm. 13C NMR
(150 MHz, CDCl3): δ = 26.5 (CH3), 33.5 (Fur-CH2), 35.3 (C-4),
45.6 (C-5), 54.1 (C-3), 112.1 (Fur-C-4), 120.4 (Fur-C-3), 140.7
(Fur-C-5), 142.6 (Fur-C-2), 213.0 (C-2) ppm. MS (EI): m/z (%) =
195 (100) [M]+, 180 (45) [M – CH3]+, 162 (16), 114 (22), 81 (60)
[FurCH2]+. HRMS (EI): calcd. for C10H13NOS [M]+ 195.0712;
found 195.0718.
mers). IR (solid): ν
= 2985, 2917, 2875, 1736, 1687 cm–1. 1H
(8RS,14RS)-8-Methyl-3-oxa-14-thia-11-azatetracyclo-
[6.6.0.01,11.02,6]tetradeca-2(6),4-dien-12-one (12): A stirred solution
of thiolactam 11 (21 mg, 0.11 mmol) in toluene (2 mL) was treated
with methyl bromoacetate (12 μL, 0.13 mmol). The reaction mix-
ture was heated at 150 °C for 18 h and then concentrated in vacuo.
Purification by flash chromatography (SiO2, 20% EtOAc in petro-
leum ether) gave tetracycle 12 (18 mg, 73%) as a yellow viscous oil.
˜
max
NMR (600 MHz, CDCl3, data for major isomer): δ = 1.33 (t, 3JH,H
2
3
= 7.2 Hz, 3 H, CH3), 2.42 (ddd, JH,H = 13.3, JH,H = 9.8, 6.2 Hz,
1 H, 6-H), 2.57 (ddd, 2JH,H = 13.3, JH,H = 9.4, 7.5 Hz, 1 H, 6-H),
3
2
3
3
3.69 (t, JH,H = JH,H = 8.2 Hz, 1 H, 4-H), 3.87 (t, JH,H = 9.6 Hz,
3
1 H, 7-H), 4.13 (tt, JH,H = 7.5, 6.5 Hz, 1 H, 5-H), 4.20–4.34 (m, 3
H, 4-H, CH2CH3), 6.32 (s, 1 H, 2-H), 7.30–7.48 (m, 5 H, Ar-
H) ppm. 13C NMR (150 MHz, CDCl3, data for major isomer): δ =
14.3 (CH3), 27.6 (C-6), 51.7 (C-7), 57.0 (C-5), 62.1 (CH2CH3), 72.0
(C-4), 87.2 (C-2), 126.0 (CH), 128.6 (CH), 128.8 (CH), 138.4 (C),
169.3 (C-8), 172.3 (CO2Et) ppm.
IR (CH2Cl2 thin film): ν
= 2960, 2922, 2864, 1683 cm–1. 1H
˜
max
2
NMR (600 MHz, CDCl3): δ = 1.34 (s, 3 H, CH3), 1.97 (dt, JH,H
3
2
3
= 13.0, JH,H = 8.4 Hz, 1 H, 9-H), 2.08 (ddd, JH,H = 12.8, JH,H
2
= 7.9, 4.1 Hz, 1 H, 9-H), 2.49 (d, JH,H = 15.2 Hz, 1 H, 7-H), 2.65
2
2
3
(d, JH,H = 15.2 Hz, 1 H, 7-H), 2.98 (dtd, JH,H = 12.0, JH,H
=
NaH (60% dispersion in oil, 620 mg, 15.3 mmol) was washed with
hexanes and then suspended in THF (80 mL) and cooled to 0 °C.
The suspension was treated with lactam 13a (13:1 mixture of dia-
stereoisomers, 3.52 g, 12.8 mmol) in THF (20 mL) , then warmed
to room temp. and stirred for 30 min. The reaction mixture was
treated with a solution of bromide 9 (prepared from 16.8 mmol of
furan-3-methanol and PBr3)[12] and stirred for 21 h. The reaction
mixture was quenched with saturated aq. NH4Cl (120 mL) and the
organic material extracted with EtOAc (3ϫ 75 mL). The combined
organic extracts were washed with water (50 mL) and brine
2
8.1, 1.1 Hz, 1 H, 10-H), 3.55 (d, JH,H = 15.2 Hz, 1 H, 13-H), 3.90
2
3
2
(ddd, JH,H = 12.0, JH,H = 8.3, 4.1 Hz, 1 H, 10-H), 4.17 (d, JH,H
3
= 15.2 Hz, 1 H, 13-H), 6.20 (d, JH,H = 1.9 Hz, 1 H, 5-H), 7.44 (d,
3JH,H = 1.9 Hz, 1 H, 4-H) ppm. 13C NMR (150 MHz, CDCl3): δ =
25.0 (CH3), 36.5 (C-13), 37.0 (C-7), 41.8 (C-9), 42.7 (C-10), 58.2
(C-8), 80.3 (C-1), 108.4 (C-5), 126.2 (C-6), 148.7 (C-4), 155.6 (C-
2), 171.0 (C-12) ppm. MS (EI): m/z (%) = 235 (75) [M]+, 220 (43)
[M – CH3]+, 175 (48), 162 (72) [M – SCH2CO]+, 146 (100). HRMS
(EI): calcd. for C12H13NO2S [M]+ 235.0662; found 235.0664.
(1S)-4-(4-Methoxyphenyl)-6-phenyl-4-thioxo-3-oxa-5-thia-7-aza- (50 mL), dried (MgSO4) and then concentrated in vacuo. Purifica-
4-phosphabicyclo[5.3.0]decane-8-thione (14): A stirred solution of
lactam 13[15] (207 mg, 1.02 mmol) in THF (5 mL) was treated with
Lawesson’s reagent (247 mg, 0.611 mmol). The mixture was heated
tion by flash chromatography (SiO2, 20% Et2O in petroleum ether)
gave lactam epi-15 (312 mg, 7%) as a colourless solid, m.p. 50–
52 °C; [α]2D0 = +165 (c 0.99, CHCl ). IR (CHCl ): ν
= 2981,
˜
max
3
3
134
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© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 129–139

Synthetic Studies Towards the Core Structure of Nakadomarin A
2938, 2876, 1736, 1708 cm–1. 1H NMR (600 MHz, CDCl3): δ =
CHCl ). IR (film): ν
= 3114 (br), 2940, 2912, 2907, 1734,
max
˜
3
3
3
3
1.27 (t, JH,H = 7.2 Hz, 3 H, CH3), 1.87 (dd, 2JH,H = 13.2, JH,H
=
1697 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.30 (t, JH,H
=
=
=
2
3
2
6.8 Hz, 1 H, 6-H), 2.78 (dd, JH,H = 13.2, JH,H = 7.2 Hz, 1 H, 6-
7.2 Hz, 3 H, CH2CH3), 2.06 (s, 3 H, CH3CO), 2.28 (dd, JH,H
2
2
3
2
3
H), 3.09 (d, JH,H = 14.8 Hz, 1 H, Fur-CH2), 3.14 (d, JH,H
=
13.9, JH,H = 8.4 Hz, 1 H, 4-H), 2.32 (dd, JH,H = 13.9, JH,H
2
3
2
14.8 Hz, 1 H, Fur-CH2), 3.18 (t, JH,H = JH,H = 7.9 Hz, 1 H, 4-
5.5 Hz, 1 H, 4-H), 3.02 (d, JH,H = 14.5 Hz, 1 H, Fur-CH2), 3.09
H), 4.14 (dd, 2JH,H = 8.0, 3JH,H = 6.3 Hz, 1 H, 4-H), 4.17–4.28 (m,
(d, JH,H = 14.5 Hz, 1 H, Fur-CH2), 3.47 (m, 1 H, 5-H), 3.93 (dd,
2
3 H, 4-H, CH2CH3), 6.25–6.28 (m, 2 H, 2-H, Fur-H), 7.27–7.43 2JH,H = 11.2, JH,H = 8.5 Hz, 1 H, AcOCH2), 4.16 (dd, JH,H
=
3
2
(m, 7 H, Ar-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 14.2 11.2, 3JH,H = 4.0 Hz, 1 H, AcOCH2), 4.24 (q, JH,H = 7.2 Hz, 2 H,
3
(CH3), 29.2 (Fur-CH2), 33.8 (C-6), 56.3 (C-5), 61.6 (C-7), 62.2
(CH2CH3), 72.1 (C-4), 87.0 (C-2), 111.9 (Fur-C-4), 119.6 (Fur-C- 1 H, Fur-H), 7.35 (t, JH,H
CH2CH3), 6.06 (br. s, 1 H, NH), 6.30 (br. s, 1 H, Fur-H), 7.30 (s,
3
=
4JH,H = 1.7 Hz, 1 H, Fur-H) ppm.
3), 126.1 (CH), 128.6 (CH), 128.8 (CH), 138.1 (C), 141.2 (Fur-C-
5), 143.3 (Fur-C-2), 170.7 (C-10), 173.0 (CO2Et) ppm. MS (CI):
m/z (%) = 356 (100) [MH]+. HRMS (CI): calcd. for C20H22NO5
[MH]+ 356.1498; found 356.1504.
13C NMR (150 MHz, CDCl3): δ = 14.2 (CH2CH3), 20.9 (CH3CO),
29.5 (Fur-CH2), 31.5 (C-4), 50.0 (C-5), 55.4 (C-3), 62.2 (CH2CH3),
67.3 (AcOCH2), 111.9 (Fur-C-4), 119.1 (Fur-C-3), 141.3 (Fur-C-
5), 143.3 (Fur-C-2), 170.7 (CH3C=O), 171.3 (CO2Et), 174.6 (C-
2) ppm. MS (CI): m/z (%) = 310 (42) [MH]+, 236 (90) [MH –
CO2Et]+, 222 (19), 203 (47), 190 (43), 81 (100) [FurCH2]+. HRMS
(CI): calcd. for C15H20NO6 [MH]+ 310.1291; found 310.1289.
Further elution (20% Et2O in petroleum ether) afforded lactam 15
(1.86 g, 41%, major isomer) as a colourless oil. [α]2D0 = +59 (c 0.81,
CHCl ). IR (CHCl ): νmax = 2981, 2939, 2878, 1740, 1704 cm–1. 1H
˜
3
3
3
NMR (600 MHz, CDCl3): δ = 1.32 (t, JH,H = 7.2 Hz, 3 H, CH3), A stirred solution of lactam 15b (285 mg, 0.92 mmol) in THF
2.32 (dd, 2JH,H = 13.9, 3JH,H = 7.9 Hz, 1 H, C6-H), 2.50 (dd, 2JH,H
(5 mL) was treated with Lawesson’s reagent (206 mg, 0.51 mmol)
and heated at reflux for 5.5 h. The reaction mixture was treated
with further Lawesson’s reagent (21 mg, 0.051 mmol) and heated at
reflux for 2 h and then concentrated in vacuo. Purification by flash
3
2
= 13.9, JH,H = 4.9 Hz, 1 H, 6-H), 3.07 (d, JH,H = 14.6 Hz, 1 H,
Fur-CH2), 3.12 (d, 2JH,H = 14.6 Hz, 1 H, Fur-CH2), 3.62 (dd, 3JH,H
= 8.7, 2JH,H = 7.9 Hz, 1 H, 4-H), 3.74 (tdd, 3JH,H = 8.5, 6.1, 4.6 Hz,
2
3
1 H, 5-H), 4.19 (dd, JH,H = 7.7, JH,H = 6.2 Hz, 1 H, 4-H), 4.22– chromatography (SiO2, 25–50 % Et2O in petroleum ether) gave
4.32 (m, 2 H, CH2CH3), 6.23 (t, 3JH,H = 4JH,H = 1.3 Hz, 1 H, Fur-
H), 6.29 (s, 1 H, 2-H), 7.27–7.38 (m, 7 H, Ar-H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 14.2 (CH3), 29.8 (Fur-CH2), 31.1 (C-6),
56.3 (C-5), 60.7 (C-7), 62.2 (CH2CH3), 71.7 (C-4), 87.3 (C-2), 112.0
(Fur-C-4), 119.2 (Fur-C-3), 126.0 (CH), 128.5 (CH), 128.8 (CH),
138.4 (C), 141.2 (Fur-C-5), 143.1 (Fur-C-2), 171.2 (C-10), 174.9
(CO2Et) ppm. MS (CI): m/z (%) = 356 (100) [MH]+. HRMS (CI):
calcd. for C20H22NO5 [MH]+ 356.1498; found 356.1507.
thiolactam 16 (197 mg, 65%) as a colourless oil. [α]2D0 = –0.8 (c =
1.25, CHCl ). IR (film): ν = 3142 (br), 2982, 2932, 2906, 1733,
˜
3
max
1515 cm–1
. =
1H NMR (600 MHz, CDCl3): δ = 1.30 (t, JH,H
3
7.2 Hz, 3 H, CH2CH3), 2.08 (s, 3 H, CH3CO), 2.35–2.42 (m, 2 H,
2
2
4-H), 3.11 (d, JH,H = 14.5 Hz, 1 H, Fur-CH2), 3.26 (d, JH,H
=
=
2
14.5 Hz, 1 H, Fur-CH2), 3.64 (m, 1 H, 5-H), 3.98 (dd, JH,H
11.2, 3JH,H = 8.9 Hz, 1 H, AcOCH2), 4.18–4.28 (m, 3 H, CH2CH3,
AcOCH2), 6.38 (br. s, 1 H, Fur-H), 7.26 (s, 1 H, Fur-H), 7.34 (s, 1
H, Fur-H), 8.04 (br. s, 1 H, NH) ppm. 13C NMR (150 MHz,
CDCl3): δ = 14.1 (CH2CH3), 20.9 (CH3CO), 32.1 (Fur-CH2), 33.2
(C-4), 58.4 (C-5), 62.3 (CH2CH3), 65.2 (C-3), 66.3 (AcOCH2),
112.0 (Fur-C-4), 119.1 (Fur-C-3), 141.4 (Fur-C-5), 143.2 (Fur-C-
2), 170.6 (CH3CO), 171.0 (CO2Et), 205.1 (CS) ppm. MS (EI): m/z
(%) = 325 (48) [M]+, 252 (100) [M – CO2Et]+, 210 (33) [M –
CH3CO]+. HRMS (EI): calcd. for C15H19NO5S [M]+ 325.0979;
found 325.0973.
Ethyl (3R,5S)-5-Acetoxymethyl-3-(furan-3-ylmethyl)-2-thioxopyr-
rolidine-3-carboxylate (16): A stirred solution of lactam 15 (557 mg,
1.57 mmol) in CH2Cl2 (42 mL) was treated with p-toluenesulfonic
acid monohydrate (298 mg, 1.57 mmol) and stirred for 105 min.
The reaction mixture was passed through a short pad of silica gel,
eluting with EtOAc to give ethyl (3R,5S)-3-(furan-3-ylmethyl)-5-
hydroxymethyl-2-oxopyrrolidine-3-carboxylate (15a, 371 mg, 87%)
as a colourless solid, m.p. 82–83 °C; [α]2D0 = +6.5 (c = 0.31, CHCl3).
IR (solid): ν
= 3227 (br), 2930, 1721, 1676 cm–1
.
1H NMR
3-Bromotetrahydro-2H-pyran-2-one (17): A stirred solution of diiso-
˜
max
3
(600 MHz, CDCl3): δ = 1.29 (t, JH,H = 7.2 Hz, 3 H, CH3), 2.24 propylamine (1.7 mL, 12 mmol) in THF (10 mL) was cooled to
2
3
2
(dd, JH,H = 13.8, JH,H = 8.7 Hz, 1 H, 4-H), 2.29 (dd, JH,H
=
0 °C and treated dropwise with n-butyllithium (2.5 m in hexanes,
4.4 mL, 11 mmol), stirred for 15 min and then cooled to –78 °C.
The solution was treated with δ-valerolactone (0.93 mL, 10 mmol)
in THF (1 mL) and stirred for 15 min. The reaction mixture was
treated with chlorotrimethylsilane (1.7 mL, 13 mmol), stirred for
1 h and then warmed to room temp. The mixture was concentrated
in vacuo and diluted with pentane (10 mL), filtered and then con-
3
3
13.8, JH,H = 5.2 Hz, 1 H, 4-H), 2.43 (br. t, JH,H = 5.5 Hz, 1 H,
2
2
OH), 3.02 (d, JH,H = 14.4 Hz, 1 H, Fur-CH2), 3.08 (d, JH,H
=
=
14.4 Hz, 1 H, Fur-CH2), 3.40 (br. m, 1 H, C-5), 3.52 (ddd, 2JH,H
3
2
11.1, JH,H = 7.0, 6.0 Hz, 1 H, CH2OH), 3.64 (ddd, JH,H = 10.9,
3JH,H = 5.3, 3.8 Hz, 1 H, CH2OH), 4.19–4.27 (m, 2 H, CH2CH3),
3
6.30 (d, JH,H = 1.3 Hz, 1 H, Fur-H), 6.49 (br. s, 1 H, NH), 7.30
(s, 1 H, Fur-H), 7.35 (t, 3JH,H = 4JH,H = 1.6 Hz, 1 H, Fur-H) ppm. centrated in vacuo once more. Purification by distillation (31–
13C NMR (150 MHz, CDCl3): δ = 14.2 (CH3), 29.6 (Fur-CH2), 32 °C, 4 Torr) gave 6-trimethylsilyloxy-3,4-dihydro-2H-pyran[30]
31.3 (C-4), 53.1 (C-5), 55.9 (C-3), 62.2 (CH2CH3), 66.0 (CH2OH), (17a; 1.32 g, 77%) as a colourless oil. IR (CDCl cast): νmax = 2956,
˜
3
111.9 (Fur-C-4), 119.2 (Fur-C-3), 141.2 (Fur-C-5), 143.3 (Fur-C-
2899, 2878 cm–1. 1H NMR (600 MHz, CDCl3): δ = 0.21 [s, 9 H,
3
2), 172.1 (C-2), 175.2 (CO2Et) ppm. MS (ES+): m/z (%) = 290 (100)
Si(CH3)3], 1.74 (m, 2 H, 3-H), 2.03 (td, JH,H = 6.4, 3.6 Hz, 2 H,
[MNa]+, 222 (50) [MNa – C4H3O]+. HRMS (ES+): calcd. for 4-H), 3.81 (t, JH,H = 3.6 Hz, 1 H, 5-H), 4.04 (br. dd, JH,H
=
3
3
C13H17NO5Na [MNa]+ 290.1004; found 290.1012.
6.0, 4.3 Hz, 2 H, 2-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 0.1
[Si(CH3)3], 20.0 (C-4), 22.5 (C-3), 67.3 (C-2), 74.1 (C-5), 154.6 (C-
6) ppm.
A stirred solution of lactam 15a (269 mg, 1.01 mmol) in CH2Cl2
(10 mL) was treated with Ac2O (105 μL, 1.1 mmol) and DMAP
(24 mg, 0.2 mmol). The reaction mixture was stirred for 80 min and
then concentrated in vacuo. Purification by flash chromatography
(SiO2, 30–50% EtOAc in petroleum ether) gave ethyl (3R,5S)-5-
acetoxymethyl-3-(furan-3-ylmethyl)-2-oxopyrrolidine-3-carb-
oxylate (15b, 298 mg, 96%) as a colourless oil. [α]2D0 = –3.0 (c = 1.0,
A stirred solution of silyl enol ether 17a (44 mg, 0.26 mmol) in
CH2Cl2 (1 mL) was cooled to –15 °C and treated dropwise with
Br2 (13 μL, 0.26 mmol). The solution was stirred for 30 min and
then concentrated in vacuo. Purification by flash chromatography
(SiO2, 30% Et2O in petroleum ether) gave lactone 17[31] (45 mg,
Eur. J. Org. Chem. 2014, 129–139
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
135

M. J. Porter et al.
FULL PAPER
3
98%) as a colourless oil. IR (CDCl cast): νmax = 2944, 2876, 2861,
(600 MHz, CDCl3): δ = 1.30 (t, JH,H = 7.1 Hz, 3 ϫ 0.6 H,
CH2CH3maj), 1.31 (t, 3JH,H = 7.2 Hz, 3ϫ0.4 H, CH2CH3min), 1.88–
˜
3
1733 cm–1. 1H NMR (600 MHz, CDCl3): δ = 1.90 (ddt, JH,H
=
2
14.6, 3JH,H = 10.5, 5.2 Hz, 1 H, 5-H), 2.25 (tdd, 2JH,H = 14.2, 3JH,H 2.00 (m, 2 H, CH2CH2O), 2.04 (s, 3ϫ0.6 H, CH3COmaj), 2.05 (s,
2
2
3
= 9.4, 5.1 Hz, 1 H, 5-H), 2.35 (m, 1 H, 4-H), 2.46 (ddt, JH,H
=
3ϫ0.4 H, CH3COmin), 2.16 (dd, JH,H = 13.3, JH,H = 8.4 Hz, 0.6
3
3
3
14.8, JH,H = 9.5, 5.2 Hz, 1 H, 4-H), 4.40 (ddd, JH,H = 11.4, 8.9,
4.5 Hz, 1 H, 3-H), 4.56–4.63 (m, 2 H, 6-H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 20.0 (C-5), 30.4 (C-4), 40.8 (C-3), 70.0 (C-
H, 3-Hmaj), 2.20 (dd, 2JH,H = 13.4, JH,H = 8.0 Hz, 0.4 H, 3-Hmin),
2
2.24–2.35 (m, 3 H, 3-H, CH2CHS), 2.91 (d, JH,H = 14.8 Hz, 0.6
H, Fur-CH2maj), 2.92 (d, 2JH,H = 14.8 Hz, 0.4 H, Fur-CH2min), 3.07
2
2
6), 166.9 (C-2) ppm. MS (CI): m/z (%) = 181/179 (78/81) [MH]+, (d, JH,H = 14.8 Hz, 0.6 H, Fur-CH2maj), 3.08 (d, JH,H = 14.8 Hz,
101 (100), 99 (100) [MH – HBr]+. HRMS (CI): calcd. for
C5H879BrO2 [MH]+ 178.9708; found 178.9702.
0.4 H, Fur-CH2min), 3.87–3.93 (m, 1.4 H, 2-H, CHSmin), 4.07 (dd,
3
2
2JH,H = 11.2, JH,H = 6.2 Hz, 0.6 H, AcOCH2maj), 4.13 (dd, JH,H
3
= 11.0, JH,H = 6.2 Hz, 0.4 H, AcOCH2min), 4.18–4.28 (m, 3 H,
2-Bromohex-5-enoyl Chloride (18): A stirred solution of diisopro-
pylamine (1.80 mL, 12.8 mmol) in THF (22 mL) was cooled to 0 °C
and then treated dropwise with n-butyllithium (2.5 m in hexanes,
5.10 mL, 12.8 mmol). The reaction mixture was stirred for 45 min,
then cooled to –10 °C and treated dropwise with hex-5-enoic
acid[30] (666 mg, 5.83 mmol) in THF (11 mL) and stirred for 2 h.
The reaction mixture was cooled to –78 °C and treated with CBr4
(3.90 g, 11.7 mmol) in THF (1 mL) and then warmed to room
temp. over 1.5 h. The reaction mixture was diluted with brine
(30 mL) and 2 m HCl (30 mL) and then extracted with Et2O (3ϫ
40 mL). The combined organic extracts were dried (MgSO4) and
then concentrated in vacuo. Purification by flash chromatography
(SiO2, 30% Et2O in petroleum ether) gave an oil which was sub-
sequently distilled under reduced pressure (1.3 Torr, 120 °C) to give
2-bromohex-5-enoic acid (18a, 517 mg, 46%) as a yellow oil. IR
AcOCH2, CH2CH3), 4.37–4.47 (m, 2 H, CHSmaj, CH2O), 4.53 (dt,
3
3
2JH,H = 10.8, JH,H = 4.3 Hz, 0.6 H, CH2O), 6.34 (d, JH,H
=
1.8 Hz, 0.4 H, Fur-Hmin), 6.35 (d, 3JH,H = 1.8 Hz, 0.6 H, Fur-Hmaj),
7.30 (s, 0.6 H, Fur-Hmaj), 7.31 (s, 0.4 H, Fur-Hmin), 7.33 (s, 0.6 H,
Fur-Hmaj), 7.34 (s, 0.4 H, Fur-Hmin) ppm. 13C NMR (150 MHz,
CDCl3): δ = 14.1 (CH2CH3min), 14.2 (CH2CH3maj), 21.03
(CH3COmaj), 21.04 (CH3COmin), 23.0 (CH2CH2Omin), 24.0
(CH2CH2Omaj), 27.2 (CH2CHSmin), 27.8 (CH2CHSmaj), 30.5 (Fur-
CH2maj), 30.7 (Fur-CH2min), 35.7 (C-3maj), 35.9 (C-3min), 43.9
(CHSmaj), 44.1 (CHSmin), 62.05 (CH2CH3maj), 62.13 (CH2CH3min),
66.3 (C-4m a j ), 66.58 (C-4mi n), 66.60 (AcOCH2m aj ), 66.7
(AcOCH2min), 69.1 (CH2Omin), 69.5 (CH2Omaj), 69.8 (C-2min), 70.0
(C-2maj), 111.7 (Fur-C-4maj), 111.8 (Fur-C-4min), 118.9 (Fur-C-
3maj), 119.0 (Fur-C-3min), 141.2 (Fur-C-2min), 141.4 (Fur-C-2maj),
143.1 (Fur-C-5min), 143.3 (Fur-C-5maj), 168.9 (SCHCOmaj), 169.3
(SCHCOmin), 170.2 (CO2Etmaj), 170.6 (CO2Etmin), 171.0 (CH3-
COmaj), 171.1 (CH3COmin), 171.3 (C-5maj), 171.4 (C-5min) ppm. MS
(CI): m/z (%) = 424 (100) [MH]+. HRMS (CI): calcd. for
C20H26NO7S [MH]+ 424.1430; found 424.1433.
(CDCl3 cast): ν
= 3081 (br), 2934, 2881, 2850, 1715 cm–1. 1H
˜
max
NMR (600 MHz, CDCl3): δ = 2.03–2.33 (m, 4 H, 3-H, 4-H), 4.27
3
3
(dd, JH,H = 8.1, 6.2 Hz, 1 H, 2-H), 5.06 (d, JH,H = 10.5 Hz, 1 H,
3
2
6-H), 5.11 (dd, JH,H = 16.9, JH,H = 1.5 Hz, 1 H, 6-H), 5.76 (ddt,
3JH,H = 17.1, 10.4, 6.6 Hz, 1 H, 5-H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 31.2 (C-4), 33.7 (C-3), 44.6 (C-2), 116.8 (C-6), 135.9
(C-5), 174.2 (C-1) ppm. MS (CI): m/z (%) = 195/193 (100) [MH]+,
177/175 (100) [MH – H2O]+, 113 (97) [MH – HBr]+. HRMS (CI):
calcd. for C6H1079BrO2 [MH]+ 192.9864; found 192.9869.
Ethyl (2E,3S,5S)-5-Acetoxymethyl-3-(furan-3-ylmethyl)-2-(2-
oxooxan-3-ylidene)pyrrolidine-3-carboxylate (20): A stirred solution
of thioimidate 19 (31 mg, 0.073 mmol) in toluene (2 mL) was
heated at 160 °C in a sealed tube for 18 h. The reaction mixture
was concentrated in vacuo. Purification by flash chromatography
(SiO2, 70% Et2O in petroleum ether) gave vinylogous carbamate
20 (23 mg, 81%) as a yellow viscous oil. [α]2D0 = +269 (c = 0.7,
A stirred solution of acid 18a (155 mg, 0.80 mmol) in CH2Cl2
(3 mL) was treated with oxalyl chloride (0.202 mL, 2.41 mmol) and
DMF (1 drop) and then stirred for 1.5 h. The reaction mixture was
concentrated in vacuo to give acyl chloride 18 (contaminated with
CHCl ). IR (film): ν
= 3364 (br), 2923, 2854, 1728 cm–1. 1H
˜
3
max
3
NMR (600 MHz, CDCl3): δ = 1.29 (t, JH,H = 7.2 Hz, 3 H,
2
DMF, 115 mg, Ͻ68%) as an oil. IR (film): νmax = 2933, 2885, 2863,
˜
CH2CH3), 1.77–1.89 (m, 2 H, CH2CH2O), 2.00 (dd, JH,H = 13.2,
1
1718, 1642 cm–1. H NMR (600 MHz, CDCl3): δ = 2.14 (m, 1 H,
3JH,H = 7.9 Hz, 1 H, 4-H), 2.06 (s, 3 H, CH3CO), 2.13–2.21 (m, 2
3
2
3-H), 2.20–2.33 (m, 3 H, 3-H, 4-H), 4.52 (dd, JH,H = 8.1, 5.5 Hz,
H, 4-H, C=C-CH2), 2.39 (m, 1 H, C=C-CH2), 3.03 (d, JH,H
=
3
3
2
1 H, 2-H), 5.10 (d, JH,H = 10.4 Hz, 1 H, 6-H), 5.13 (dd, JH,H
=
14.9 Hz, 1 H, Fur-CH2), 3.07 (d, JH,H = 14.9 Hz, 1 H, Fur-CH2),
2
3
3
2
16.9, JH,H = 1.1 Hz, 1 H, 6-H), 5.75 (ddt, JH,H = 16.9, 10.4,
6.4 Hz, 1 H, 5-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 30.9 (C-
4), 33.8 (C-3), 53.6 (C-2), 117.5 (C-6), 135.3 (C-5), 170.3 (C-1) ppm.
MS (CI): m/z (%) = 209/207 (82), 177/175 (15) [MH – HCl]+, 163
(48), 127 (100).
3.46 (qd, JH,H = 7.8, 3.8 Hz, 1 H, 5-H), 3.82 (dd, JH,H = 11.1,
2
3
3JH,H = 7.9 Hz, 1 H, AcOCH2), 4.09 (dd, JH,H = 11.1, JH,H
=
4.1 Hz, 1 H, AcOCH2), 4.20–4.30 (m, 4 H, CH2CH3, CH2CH2O),
6.21 (br. s, 1 H, Fur-H), 7.28 (s, 1 H, Fur-H), 7.33 (t, 2JH,H = 3JH,H
= 1.5 Hz, 1 H, Fur-H), 9.43 (s, 1 H, NH) ppm. 13C NMR
(150 MHz, CDCl3): δ = 14.3 (CH2CH3), 20.9 (CH3CO), 23.0
(C=CCH2), 23.2 (CH2CH2O), 29.4 (Fur-CH2), 37.1 (C-4), 56.5 (C-
5), 57.7 (C-3), 62.0 (CH2CH3), 67.0 (AcOCH2), 68.4 (CH2CH2O),
83.9 (NC=C), 112.0 (Fur-C-4), 118.7 (Fur-C-3), 141.3 (Fur-C-5),
143.5 (Fur-C-2), 164.9 (NC=C), 169.7 (C=CCO), 170.9 (CH3CO),
173.4 (CO2Et) ppm. MS (CI): m/z (%) = 392 (100) [MH]+. HRMS
(CI): calcd. for C20H26NO7 [MH]+ 392.1909; found 392.1706.
Ethyl (2S,4R)-2-Acetoxymethyl-4-(furan-3-ylmethyl)-5-(2-oxooxan-
3-ylsulfanyl)-3,4-dihydro-2H-pyrrole-4-carboxylate (19): NaH (60%
dispersion in oil, 58 mg, 1.45 mmol) was washed with hexanes and
then suspended in THF (7 mL), cooled to 0 °C and treated drop-
wise with a solution of thiolactam 16 (394 mg, 1.21 mmol) in THF
(2 mL) and then stirred for 30 min. The reaction mixture was
treated dropwise with a solution of lactone 17 (234 mg, 1.31 mmol)
in THF (1 mL) and then warmed to room temp. The reaction mix-
ture was stirred for 1.5 h and then diluted with H2O (12 mL). The
organic material was extracted with EtOAc (4ϫ 15 mL) and the
organic extracts were combined, washed with brine (2ϫ 15 mL),
dried (MgSO4) and then concentrated in vacuo to give thioimidate
Ethyl (1R,8R,10S)-10-Acetoxymethyl-13-(but-3-enyl)-12-oxo-3-oxa-
14-thia-11-azatetracyclo[6.6.0.01,11.02,6]tetradeca-2(6),4-diene-8-
carboxylate (21) and Ethyl (3E,6R,8S)-8-Acetoxymethyl-3-(but-3-
enylidene)-6-(furan-3-ylmethyl)-2-oxo-4-thia-1-azabicyclo[3.3.0]-
octane-6-carboxylate (22): A stirred solution of thiolactam 16
19 (6:4 mixture of diastereomers, 340 mg, 66 %) as a brown oil (136 mg, 0.418 mmol) in toluene (2 mL) was treated with acyl
which was used in the next step without further purification. IR chloride 18 (129 mg, 0.610 mmol) in toluene (2 mL). The reaction
(CDCl3 cast): ν
= 2924, 2872, 2854, 1729 cm–1 1H NMR mixture was heated at reflux for 7 h and then concentrated in
.
˜
max
136
www.eurjoc.org
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 129–139

Synthetic Studies Towards the Core Structure of Nakadomarin A
vacuo. Purification by flash chromatography (SiO2, 10–20% EtOAc
by flash chromatography (SiO2, 50–75% Et2O in hexane) gave acet-
in hexane) gave bicycle 22 (64 mg, 36%) as a yellow oil. [α]2D0 = –19
onide 27 (10.6 g, 72%) as a colourless solid, m.p. 24–25 °C (ref.[17]
(c = 1.0, CHCl ). IR (film): ν
= 2937, 2907, 2882, 1738, 1683, = 36–37 °C). IR (solid): ν
= 2980, 2933, 2888, 1670 cm–1. 1H
˜
˜
3
max
max
3
1634 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.30 (t, JH,H
=
=
NMR (600 MHz, CDCl3): δ = 1.45 (s, 3 H, CH3), 1.65 (s, 3 H,
2
2
3
7.2 Hz, 3 H, CH2CH3), 2.08 (s, 3 H, CH3CO), 2.26 (ddd, JH,H
CH3), 1.75 (tt, JH,H = 12.2, JH,H = 12.2, 9.0 Hz, 1 H, 6-H), 2.16
3
2
3
2
3
13.9, JH,H = 8.7, 1.2 Hz, 1 H, 7-H), 2.35 (dd, JH,H = 13.9, JH,H
(m, 1 H, 6-H), 2.53 (dd, JH,H = 16.6, JH,H = 9.1 Hz, 1 H, 7-H),
3
2
3
= 7.7 Hz, 1 H, 7-H), 2.90 (br. t, JH , H = 6.9 Hz, 2 H,
2.79 (ddd, JH,H = 16.6, JH,H = 12.1, 8.5 Hz, 1 H, 7-H), 3.44 (t,
CH2=CHCH2), 3.20 (d, 2JH,H = 14.9 Hz, 1 H, Fur-CH2), 4.11–4.33
2JH,H = JH,H = 8.8 Hz, 1 H, 4-H), 4.07 (dd, JH,H = 8.2, JH,H
=
3
2
3
3
3
(m, 5 H, AcOCH2, 8-H, CH2CH3), 5.08 (br. d, JH,H = 10.1 Hz, 1
5.7 Hz, 1 H, 4-H), 4.25 (tt, JH,H = 8.8, 6.0 Hz, 1 H, 5-H) ppm.
3
H, CH=CH2), 5.14 (br. d, JH,H = 17.0 Hz, 1 H, CH=CH2), 5.20 13C NMR (150 MHz, CDCl3): δ = 23.9 (CH3), 24.4 (C-6), 26.9
(s, 1 H, 5-H), 5.82 (ddt, 3JH,H = 16.9, 10.1, 6.3 Hz, 1 H, CH=CH2),
(CH3), 37.3 (C-7), 61.7 (C-5), 70.0 (C-4), 91.4 (C-2), 171.6 (C-
8) ppm.
3
6.13 (s, 1 H, Fur-H), 6.78 (t, JH,H = 7.4 Hz, 1 H, C=CH), 7.20 (s,
1 H, Fur-H), 7.35 (br. s, 1 H, Fur-H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 14.3 (CH2CH3), 21.0 (CH3CO), 25.5 (Fur-CH2), 33.3
(C-7), 34.7 (CH2=CHCH2), 53.4 (C-8), 55.1 (C-6), 61.9 (CH2CH3),
64.9 (AcOCH2), 67.3 (C-5), 111.5 (Fur-C-4), 116.9 (CH2=CH),
118.6 (Fur-C-3), 126.4 (C=CH), 130.9 (C=CH), 133.2 (CH2=CH),
140.9 (Fur-C-2), 143.3 (Fur-C-5), 166.4 (C-2), 170.8 (CH3CO),
172.1 (CO2Et) ppm. MS (CI): m/z (%) = 420 (100) [MH]+. HRMS
(CI): calcd. for C21H26NO6S [MH]+ 420.1481; found 420.1479.
Ethyl (5S)-2,2-Dimethyl-8-oxo-3-oxa-1-azabicyclo[3.3.0]octane-7-
carboxylate (28): A flask charged with LHMDS (1 m in toluene,
0.64 mL, 0.64 mmol) at –78 °C was treated dropwise with a solu-
tion of lactam 27 (500 mg, 0.322 mmol) and diethyl carbonate
(0.507 mL, 4.19 mmol) in THF (12 mL) over 30 min. The reaction
mixture was stirred for 1 h and then warmed to 0 °C and quenched
with AcOH (0.92 mL). Et2O (12 mL) was added and the mixture
was concentrated in vacuo. Purification by flash chromatography
(SiO2, 70% Et2O in hexane) gave ester 28 (663 mg, 91%, 6:4 mix-
Further elution (20% EtOAc in hexane) gave tetracycle 21 (37 mg,
21%, 4:1 ratio of diastereoisomers) as a yellow oil. IR (film): ν
˜
max
ture of diastereoisomers) as a colourless oil. IR (film): νmax = 2984,
˜
= 2937, 2907, 2878, 1734, 1685, 1640 cm–1. 1H NMR (600 MHz,
2938, 2873, 1735, 1694 cm–1. 1H NMR (600 MHz, CDCl3): δ =
1.30 (t, 3JH,H = 7.2 Hz, 1.2 H, CH2CH3min), 1.31 (t, 3JH,H = 7.2 Hz,
CDCl3): δ = 1.30 (t, JH,H = 6.8 Hz, 2.4 H, CH2CH3maj), 1.32 (t,
3
3JH,H = 7.2 Hz, 0.6 H, CH2CH3min), 1.75 (m, 0.8 H, SCHCH2maj),
2.06 (s, 2.4 H, CH3COmaj), 2.07 (s, 0.6 H, CH3COmin), 2.09–2.15
(m, 1.8 H, CH2=CHCH2maj, SCHCH2min), 2.15–2.20 (m, 1 H, 9-
H), 2.21–2.37 (m, 1.4 H, SCHCH2, CH2=CHCH2min), 2.60 (d,
1.8 H, CH2CH3maj), 1.46 (s, 1.8 H, CH3maj), 1.46 (s, 1.2 H, CH3min),
2
1.65 (s, 1.8 H, CH3maj), 1.66 (s, 1.2 H, CH3min), 1.96 (dt, JH,H
=
12.9, JH,H = 8.8 Hz, 0.4 H, 6-Hmin), 2.24 (td, JH,H = 12.1, JH,H
3
2
3
= 8.8 Hz, 0.6 H, 6-Hmaj), 2.36 (ddd, JH,H = 12.6, JH,H = 7.7,
2
3
2
2JH,H = 15.1 Hz, 0.2 H, 7-Hmin), 2.61 (d, JH,H = 15.4 Hz, 0.8 H,
6.2 Hz, 0.6 H, 6-Hmaj), 2.49 (dd, JH,H = 12.7, JH,H = 6.2 Hz, 0.4
3
3
2
3
7-Hmaj), 2.89 (dd, JH,H = 13.4, JH,H = 8.7 Hz, 0.2 H, 9-Hmin),
H, 6-Hmin), 3.45 (t, JH,H
=
3JH,H = 8.9 Hz, 0.4 H, 4-Hmin), 3.55
2
2.99 (dd, JH,H = 13.6, JH,H = 8.7 Hz, 0.8 H, 9-Hmaj), 3.36 (d,
2
3
3
(t, 2JH,H = 3JH,H = 8.8 Hz, 0.6 H, 4-Hmaj), 3.60 (d, JH,H = 9.2 Hz,
0.4 H, 7-Hmin), 3.81 (dd, 3JH,H = 11.7, 8.0 Hz, 0.6 H, 7-Hmaj), 4.07–
4.14 (m, 1 H, 4-H), 4.14–4.30 (m, 2.6 H, CH2CH3, 5-Hmaj), 4.47
(tt, 3JH,H = 8.9, 6.1 Hz, 0.4 H, 5-Hmin) ppm. 13C NMR (150 MHz,
CDCl3): δ = 14.2 (CH2CH3min), 14.3 (CH2CH3maj), 23.7 (CH3min),
23.8 (CH3maj), 26.7 (CH3min), 26.8 (CH3maj), 28.0 (C-6maj), 28.2 (C-
6min), 54.2 (C-7maj), 55.3 (C-7min), 59.2 (C-5maj), 60.8 (C-5min), 61.8
(CH2CH3maj), 61.9 (CH2CH3min), 69.8 (C-4maj), 69.9 (C-4min), 91.8
(C-2min), 91.9 (C-2maj), 166.0 (C-8min), 166.4 (C-8maj), 169.5
(CO2Etmaj), 169.7 (CO2Etmin) ppm. MS (ES+): m/z (%) = 250 (50)
[MNa]+. HRMS (ES+): calcd. for C11H17NO4Na [MNa]+ 250.1055;
found 250.1055.
2JH,H = 15.4 Hz, 0.8 H, C7-Hmaj), 3.40 (d, JH,H = 15.1 Hz, 0.2 H,
2
7-Hmin), 3.73 (m, 0.8 H, 10-Hmaj), 3.77 (dd, JH,H = 10.0, 3.8 Hz,
3
0.2 H, 13-Hmin), 4.14 (dd, JH,H = 11.3, JH,H = 5.2 Hz, 0.2 H,
2
3
AcOCH2 m i n ), 4.18–4.31 (m, 1.4 H, CH2 CH3 , 10-Hm i n
,
AcOCH2min), 4.38 (dd, JH,H = 9.3, 3.7 Hz, 0.8 H, 13-Hmaj), 4.55
3
2
3
(dd, JH,H = 11.3, JH,H = 6.7 Hz, 0.8 H, AcOCH2maj), 4.92 (dd,
2JH,H = 11.3, JH,H = 4.4 Hz, 0.8 H, AcOCH2maj), 4.99–5.08 (m, 2
3
3
H, CH2=CH), 5.74–5.84 (m, 1 H, CH2=CH), 6.23 (d, JH,H
=
2.0 Hz, 0.8 H, 5-Hmaj), 6.24 (d, 3JH,H = 2.0 Hz, 0.2 H, 5-Hmin), 7.43
(d, 3JH,H = 2.0 Hz, 0.8 H, 4-Hmaj), 7.47 (d, 3JH,H = 2.0 Hz, 0.2 H, 4-
Hmin) ppm. 13C NMR (150 MHz, CDCl3): δ = 14.32 (CH2CH3min),
14.36 (CH2CH3maj), 21.01 (COCH3maj), 21.04 (COCH3min), 31.3
(CH2=CHCH2), 31.9 (SCHCH2min), 32.0 (SCHCH2maj), 33.4 (C-
7min), 34.4 (C-7maj), 42.1 (C-9maj), 43.1 (C-9min), 51.1 (C-13maj), 51.9
(C-13min), 55.4 (C-10maj), 56.0 (C-10min), 61.8 (AcOCH2maj), 61.95
(AcOCH2min), 62.0 (CH2CH3min), 62.1 (CH2CH3maj), 66.3 (C-8maj),
67.0 (C-8min), 78.0 (C-1maj), 79.4 (C-1min), 108.3 (C-5maj), 108.5 (C-
5min), 116.08 (CH2=CHmaj), 116.13 (CH2=CHmin), 125.8 (C-6maj),
126.6 (C-6min), 136.9 (CH2=CHmaj), 137.1 (CH2=CHmin), 149.3
(C-4maj), 149.7 (C-4min), 153.4 (C-2min), 154.5 (C-2maj), 170.7 (C-
12maj), 170.8 (CH3COmaj), 170.9 (CH3COmin), 171.8 (C-12min),
171.9 (CO2Etmaj), 172.0 (CO2Etmin) ppm. MS (CI): m/z (%) = 420
(100) [MH]+, 378 (16), 360 (52) [MH – HOAc]+, 292 (22). HRMS
(CI): calcd. for C21H26NO6S [MH]+ 420.1481; found 420.1475.
(5S)-2,2-Dimethyl-3-oxa-1-azabicyclo[3.3.0]octane-8-thione (29): A
stirred solution of ethyl l-pyroglutamate (30;[21] 2.00 g, 12.7 mmol)
in THF (30 mL) was treated with Lawesson’s reagent (2.60 g,
6.33 mmol) and then stirred for 2 h. The reaction mixture was con-
centrated in vacuo. Purification by repeated flash chromatography
(SiO2, 40% EtOAc in hexane and then SiO2, 65% Et2O in hexane)
gave ethyl (S)-5-thioxopyrrolidine-2-carboxylate (30a; 1.80 g, 82%)
as a colourless solid, m.p. 37–38 °C (ref.[22] = 35–36 °C). IR (solid):
1
ν
˜
= 3300 (br), 2982, 2941, 2875, 1743, 1716, 1524 cm–1. H
max
3
NMR (600 MHz, CDCl3): δ = 1.30 (t, JH,H = 7.2 Hz, 3 H, CH3),
2
3
2.35 (ddt, JH,H = 13.2, JH,H = 9.3, 6.7 Hz, 1 H, 3-H), 2.56 (dtd,
2JH,H = 13.2, JH,H = 8.9, 5.9 Hz, 1 H, 3-H), 2.92 (ddd, JH,H
=
3
2
18.2, 3JH,H = 9.0, 7.3 Hz, 1 H, 4-H), 2.99 (ddd, 2JH,H = 18.2, 3JH,H
= 9.4 6.0 Hz, 1 H, 4-H), 4.20–4.29 (m, 2 H, CH2CH3), 4.51 (dd,
3JH,H = 8.7, 6.4 Hz, 1 H, 2-H), 8.10 (br. s, 1 H, NH) ppm. 13C
NMR (150 MHz, CDCl3): δ = 14.2 (CH3), 27.2 (C-3), 42.7 (C-4),
62.3 (CH2CH3), 62.6 (C-2), 170.1 (CO2Et), 206.8 (C-5) ppm.
(5S)-2,2-Dimethyl-3-oxa-1-azabicyclo[3.3.0]octan-8-one (27):[18]
A
stirred suspension of l-pyroglutaminol (10.9 g, 94.7 mmol) in tolu-
ene (100 mL) was treated with 2,2-dimethoxypropane (15.1 mL,
123 mmol) and p-toluenesulfonic acid (360 mg, 1.89 mmol) and
then heated at reflux for 2 h. MeOH was removed from the reaction
mixture by distillation and further 2,2-dimethoxypropane
(15.1 mL, 123 mmol) was added. The reaction mixture was heated
at reflux for 30 min and then concentrated in vacuo. Purification
A stirred solution of ester 30a (11.1 g, 64.1 mmol) in THF
(100 mL) was treated with LiBH4 (1.50 g, 70.5 mmol) and then
stirred for 1 h. The reaction mixture was cooled to 0 °C and treated
Eur. J. Org. Chem. 2014, 129–139
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
137

M. J. Porter et al.
FULL PAPER
with 20% aqueous acetic acid (40 mL) and then adsorbed onto
silica gel. Purification by flash chromatography (SiO2, 6% MeOH
in CHCl3) gave (S)-5-hydroxymethylpyrrolidine-2-thione (30b;
7.43 g, 88%) as a colourless solid, m.p. 125–126 °C (ref.[22] = 124–
(5S,7S,1ЈR)-2,2-Dimethyl-N-phenyl-7-(1-phenylprop-2-enyl)-8-thi-
oxo-3-oxa-1-azabicyclo[3.3.0]octane-7-carboxamide (37): A stirred
solution of thioamide 29 (141 mg, 0.824 mmol) in THF (2 mL) at
0 °C was treated with n-butyllithium (2.02 m in hexanes, 0.40 mL,
125 °C). IR (solid): ν
= 3178 (br), 3046 (br), 2973, 2932, 2877, 0.81 mmol) and then stirred for 25 min. The reaction mixture was
˜
max
1532 cm–1. 1H NMR (600 MHz, [D6]DMSO): δ = 1.85 (dddd, 2JH,H
cooled to –78 °C and then treated with (Z)-cinnamyl bromide
(195 mg, 0.99 mmol) in THF (2 mL). The reaction mixture was
stirred for 15 min and then warmed to 0 °C and treated with AcOH
(3 μL, 50 μmol) followed immediately by PhNCO (120 μL,
1.1 mmol). The reaction mixture was warmed to room temp. over
18 h and then quenched with brine (4 mL). The organic material
was extracted with CH2Cl2 (3ϫ5 mL) and the combined extracts
were dried (hydrophobic frit) and then concentrated in vacuo. Puri-
fication by flash chromatography (SiO2, 13% EtOAc in hexane)
gave thioamide 37 (155 mg, 46%, 96% de) as a colourless solid.
3
3
= 12.8, JH,H = 9.4, 6.0, 5.3 Hz, 1 H, 4-H), 2.09 (dddd, JH,H
=
3
2
12.7, JH,H = 9.6, 8.4, 6.6 Hz, 1 H, 4-H), 2.65 (ddd, JH,H = 17.8,
3JH,H = 9.8, 6.4 Hz, 1 H, 3-H), 2.73 (ddd, JH,H = 18.1, JH,H
=
2
3
9.4, 6.4 Hz, 1 H, 3-H), 3.37–3.44 (m, 2 H, CH2OH), 3.84 (dt, 3JH,H
= 13.2, 4.5 Hz, 1 H, 5-H), 4.91 (t, 3JH,H = 5.5 Hz, 1 H, OH), 10.12
(br. s, 1 H, NH) ppm. 13C NMR (150 MHz, [D6]DMSO): δ = 24.7
(C-4), 43.2 (C-3), 62.7 (CH2OH), 63.6 (C-5), 203.7 (C-2) ppm.
A stirred suspension of thiolactam 30b (0.40 g, 3.1 mmol) in tolu-
ene (4 mL) was treated with 2,2-dimethoxypropane (0.487 mL,
3.96 mmol) and p-toluenesulfonic acid (12 mg, 0.061 mmol). The
mixture was heated at reflux for 3 h and then concentrated in
vacuo. Purification by flash chromatography (SiO2, 30–50% Et2O
in petroleum ether) gave bicycle 29 (268 mg, 51%) as a colourless
solid, m.p. 74–75 °C; [α]2D0 = +241 (c = 1.0, CHCl3). IR (CHCl3
M.p 116–117 °C; [α]2D5 = +56.8 (c = 1.02, CHCl ). IR (solid): ν
˜
3
max
= 3184, 2986, 2926, 2863, 1670, 1549 cm–1. 1H NMR (600 MHz,
CDCl3): δ = 1.56 (s, 3 H, CH3), 1.77 (s, 3 H, CH3), 2.39 (dd, 2JH,H
= 13.6, JH,H = 9.9 Hz, 1 H, 6-H), 2.59 (dd, JH,H = 13.6, JH,H
6.6 Hz, 1 H, 6-H), 2.95 (tt, JH,H = 10.1, 6.0 Hz, 1 H, 5-H), 3.26
(dd, 3JH,H = 10.3, 2JH,H = 8.5 Hz, 1 H, 4-H), 3.86 (dd, 2JH,H = 8.5,
3JH,H = 5.5 Hz, 1 H, 4-H), 4.01 (d, 3JH,H = 9.6 Hz, 1 H, 1Ј-H), 5.08
3
2
3
=
3
cast): ν
= 2987, 2940, 2871, 1476 cm–1. 1H NMR (600 MHz,
˜
max
2
3
CDCl3): δ = 1.67 (s, 3 H, CH3), 1.80 (tdd, JH,H = 12.2, JH,H
=
=
=
3
2
3
(dd, JH,H = 10.1, JH,H = 1.2 Hz, 1 H, 3Ј-H), 5.12 (d, JH,H
=
2
12.2, 10.3, 8.5 Hz, 1 H, 6-H), 1.83 (s, 3 H, CH3), 2.17 (dt, JH,H
16.8 Hz, 1 H, 3Ј-H), 6.69 (dt, 3JH,H = 16.8, 9.8 Hz, 1 H, 2Ј-H), 7.11
3
2
3
12.2, JH,H = 6.3 Hz, 1 H, 6-H), 3.25 (dd, JH,H = 17.3, JH,H
3
4
(tt, JH,H = 7.3, JH,H = 1.1 Hz, 1 H, Ar-H), 7.28–7.36 (m, 5 H,
Ar-H), 7.43 (m, 2 H, Ar-H), 7.55 (m, 2 H, Ar-H), 11.31 (s, 1 H,
NH) ppm. 13C NMR (150 MHz, CDCl3): δ = 22.0 (CH3), 24.0
(CH3), 33.5 (C-6), 59.9 (C-1Ј), 64.4 (C-5), 68.6 (C-4), 77.1 (C-7),
94.5 (C-2), 118.1 (C-3Ј), 120.1 (CH), 124.5 (CH), 128.2 (CH), 128.9
(CH), 129.0 (CH), 129.1 (CH), 136.1 (C-2Ј), 137.7 (C), 138.7 (C),
168.7 (CONH), 192.9 (C-8) ppm. MS (CI): m/z (%) = 407 (8) -
[MH]+, 349 (23) [MH – OC(CH3)2]+, 291 (100), 233 (73), 119 (28),
82 (69), 56 (28). HRMS (CI): calcd. for C24H27N2O2S [MH]+
407.1793; found 407.1796.
2
3
8.4 Hz, 1 H, 7-H), 3.34 (ddd, JH,H = 17.3, JH,H = 12.5, 7.3 Hz, 1
3
2
H, 7-H), 3.53 (dd, JH,H = 10.0, JH,H = 8.6 Hz, 1 H, 4-H), 4.10
2
3
3
(dd, JH,H = 8.6, JH,H = 5.5 Hz, 1 H, 4-H), 4.49 (tt, JH,H = 10.5,
5.5 Hz, 1 H, 5-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 22.2
(CH3), 24.9 (CH3), 26.1 (C-6), 52.5 (C-7), 68.0 (C-4), 69.6 (C-5),
93.4 (C-2), 195.8 (C-8) ppm. MS (CI): m/z (%) = 172 (100)
[MH]+. HRMS (CI): calcd. for C8H14NOS [MH]+ 172.0796; found
172.0791. C8H14NOS (171.26): C 56.10, H 7.65, N 8.18, found C
56.22, H 7.71, N 8.16.
(5S,7S,1ЈR)-2,2-Dimethyl-7-(1-phenylprop-2-enyl)-3-oxa-1-azabi-
cyclo[3.3.0]octane-8-thione (36): A stirred solution of thioamide 29
(205 mg, 1.20 mmol) in THF (5 mL) at 0 °C was treated with n-
butyllithium (2.5 m in hexane, 0.55 mL, 1.3 mmol) and then stirred
for 15 min. The reaction mixture was treated with cinnamyl brom-
ide (260 mg, 1.32 mmol) in THF (1 mL) and stirred at 0 °C for
30 min and then at room temp. for 1 h. A saturated aq. NaHCO3
solution (6 mL) was added and the organic material extracted with
Et2O (3ϫ6 mL). The combined organic extracts were washed with
brine (6 mL), dried (MgSO4) and then concentrated in vacuo. Puri-
fication by flash chromatography (SiO2, 20% Et2O in hexane) gave
thioamide 36 (252 mg, 73%, 92% de) as a colourless solid, m.p.
Supporting Information (see footnote on the first page of this arti-
1
cle): 1D H and 13C NMR spectra, and selected 2D NMR spectra
of all compounds synthesised.
Acknowledgments
The authors thank Dr. Abil Aliev for assistance with NMR spec-
troscopy, and Dr. Lisa Haigh for mass spectrometry. The Engineer-
ing and Physical Sciences Research Council is thanked for an In-
dustrial CASE Award.
119–120 °C; [α]2D0 = –94 (c = 0.35, CHCl ). IR (CH Cl cast): ν
˜
3
2
2
max
= 2984, 2928, 2869, 1484 cm–1. H NMR (600 MHz, CDCl3, data
for major diastereoisomer): δ = 1.40 (s, 3 H, CH3), 1.80 (s, 3 H,
CH3), 1.90 (dt, 2JH,H = 12.7, 3JH,H = 9.7 Hz, 1 H, C6-H), 2.09 (dd,
1
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128.4 (CH), 128.9 (CH), 138.8 (C-2Ј), 139.5 (C), 197.6 (C-8) ppm.
MS (EI): m/z (%) = 287 (23) [M]+, 117 (17) [PhCHCH=CH2]+, 86
(100). HRMS (EI): calcd. for C17H21NOS [M]+ 287.1339; found
287.1341.
138
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© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 129–139

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Received: July 17, 2013
Published Online: November 14, 2013
Eur. J. Org. Chem. 2014, 129–139
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
139