A three-step tandem process for the synthesis of bicyclic γ-lactams

Article abstract of DOI:10.1039/c004695g

A one-pot, three-step tandem process has been developed for the direct synthesis of functionalised bicyclic [3.3.0], [4.3.0] and [5.3.0] γ-lactams from simple allylic trichloroacetimidates. The process involves a palladium(ii) mediated Overman rearrangement followed by the use of Grubbs first generation complex which catalyzes both a ring closing metathesis reaction and a Kharasch cyclization. As well as exploring the scope of this process for the synthesis of a range of functionalised bicyclic γ-lactams, the use of chiral palladium(ii) catalysts during the Overman rearrangement for the enantioselective synthesis of the bicyclic γ-lactams is also demonstrated. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c004695g

Organic &
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Volume 8 | Number 15 | 7 August 2010 | Pages 3345–3580
ISSN 1477-0520
EMERGING AREA
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Applications of dynamic nuclear
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FULL PAPER
Andrew Sutherland et al.
A Three-Step Tandem Process For The
Synthesis of Bicyclic ␥-Lactams
1477-0520(2010)8:15;1-Z

PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A three-step tandem process for the synthesis of bicyclic c-lactams†
Fiona I. McGonagle,a Lindsay Brown,b Andrew Cookeb and Andrew Sutherland*a
Received 29th March 2010, Accepted 4th May 2010
First published as an Advance Article on the web 28th May 2010
DOI: 10.1039/c004695g
A one-pot, three-step tandem process has been developed for the direct synthesis of functionalised
bicyclic [3.3.0], [4.3.0] and [5.3.0] g-lactams from simple allylic trichloroacetimidates. The process
involves a palladium(II) mediated Overman rearrangement followed by the use of Grubbs first
generation complex which catalyzes both a ring closing metathesis reaction and a Kharasch cyclization.
As well as exploring the scope of this process for the synthesis of a range of functionalised bicyclic
g-lactams, the use of chiral palladium(II) catalysts during the Overman rearrangement for the
enantioselective synthesis of the bicyclic g-lactams is also demonstrated.
Introduction
Tandem or cascade processes have become a powerful tool for
performing several chemical reactions in only one operation
often yielding products with significantly increased molecular
complexity.1,2 Furthermore, these processes circumvent the time-
intensive and yield reducing isolation and purification of interme-
diates in conventional multiple-step syntheses and their general
use results in a reduction in waste generation which has obvious
benefits for the environment.3 While a variety of transformations
have been utilised for tandem processes, pericyclic or metathesis
reactions have featured prominently.1,4,5 This is mainly due to the
highly selective and efficient nature of most pericyclic processes
and the continued development of stable and commercially
available ruthenium alkylidene complexes for metathesis reactions.
Our own research efforts have resulted in the development of
a highly efficient one-pot tandem process involving the Overman
Scheme 1 Proposed one-pot tandem synthesis of bicyclic g-lactams.
rearrangement of allylic trichloroacetimidates6 followed by ring
closing metathesis (RCM) of the resulting trichloroacetamide
derived dienes to give functionalized carbocyclic amides of
various ring sizes.7 Asymmetric variants have also been developed
and utilized in natural product synthesis.7,8 The carbocyclic
trichloroacetamides formed from this tandem process are excellent
substrates for the ruthenium(II) catalyzed Kharasch cyclization
which allows the preparation of g-lactams via an atom transfer
radical mechanism.8a,9 As the second step of our tandem process
and the Kharasch cyclization both use a ruthenium(II) catalyst, it
was proposed that our original one-pot two-step tandem process
could be extended to include the Kharasch cyclization (Scheme 1).
Such a process would allow the direct one-pot synthesis of
bicyclic g-lactams from simple allylic alcohol precursors using
a palladium(II) complex to catalyze the Overman rearrangement
and a ruthenium(II) complex to effect both the RCM and Kharasch
steps. Our confidence in developing such a process came from
work reported by the research groups of Schmidt,10 Snapper11
and Quayle12 which utilized ruthenium mediated tandem catalytic
processes13 for the preparation of g-lactams and g-lactones from
trihaloacetamide and trihaloacetate derived dienes, respectively.
In this paper, we now report the development of a one-pot,
three step tandem process for the diastereoselective synthesis of
functionalised bicyclic [3.3.0], [4.3.0] and [5.3.0] g-lactams. The
use of chiral palladium(II) catalysts during the first step of this
tandem process for the enantioselective synthesis of bicyclic [3.3.0]
and [4.3.0] g-lactams is also described.
Results and discussion
To fully examine the scope of the tandem process, a series of allylic
alcohols were prepared in three steps (Scheme 2). A one-pot Swern
oxidation and Horner–Wadsworth–Emmons (HWE) reaction14,15
was used to generate (E)-a,b-unsaturated esters in good yields
over the two steps from either commercially available or known
alcohols.16,17 Subsequent reduction of the (E)-a,b-unsaturated
esters using DIBAL-H gave the desired allylic alcohols.
The development of the three-step tandem process was carried
out using (2E)-octa-2,7-dien-1-ol (1) (Scheme 3). Allylic alcohol
1 was converted to the corresponding allylic trichloroacetimidate
2 using trichloroacetonitrile and a catalytic amount of DBU.18
aWestCHEM, Department of Chemistry, The Joseph Black Building,
University of Glasgow, Glasgow, UK G12 8QQ
bSchering-Plough Research Institute, Newhouse, Motherwell, UK ML1 5SH.
E-mail: andrews@chem.gla.ac.uk
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra for 4, 6, 8, 10 and 12 and all new compounds.
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©

catalyst may have decomposed before completion of the Kharasch
cyclization. To overcome this, an additional quantity of Grubbs
first generation catalyst (5 mol%) was added at the start of the
Kharasch cyclization (entry 2), resulting in an increased yield
of 73% for lactam 4. Instead of using additional Grubbs first
generation catalyst, a similar yield of 71% could be achieved for
lactam 4 using just 10 mol% of catalyst for both steps and by doing
the RCM reaction at room temperature (entry 3). In this case
only lactam 4 was isolated suggesting that the lower temperature
used for the RCM step prolongs the lifetime of the Grubbs first
generation catalyst allowing better overall conversion. The high
temperatures used for the Kharasch cyclization can lead to the
generation of hydrochloric acid resulting in partial decomposition
of both starting materials and products. During previous studies
on the Kharasch cyclization of cyclic allylic trichloroacetamides
Scheme 2 Reagents and conditions: i. (COCl)2, DMSO, Et3N, CH2Cl2; ii.
DBU, LiCl, (EtO)2POCH2CO2Et, MeCN, 50–79% over the two steps; iii.
DIBAL-H, Et2O, 76–90%.
˚
we have found that the addition of 4 A molecular sieves as an
acid scavenger21 allowed the reproducible synthesis of bicyclic
g-lactams in high yields.8a Thus, the conditions used for entry 3
˚
were further modified by the addition of 4 A molecular sieves at
the Kharasch cyclization step (entry 4) and this led to the isolation
of lactam 4 in an excellent 87% yield from allylic alcohol 1.
The optimized conditions were then used to explore the scope of
the three-step tandem process (Table 1). Conversion of (2E)-hepta-
2,6-dien-1-ol to the corresponding allylic trichloroacetimidate 5
followed by the three-step tandem sequence gave bicyclic [3.3.0]
lactam 6 in 71% yield (entry 1). The bicyclic [5.3.0] lactam 8 was
prepared in 60% yield over the four steps, however the RCM
step required higher catalyst loading (25 mol%) and more forcing
conditions than analogues 4 and 6 (entry 3). The bicyclic [4.3.0]
lactams 10 and 12 containing ether and amine functionalities
were also prepared using the one-pot tandem process but in
only 36% and 19% overall yield, respectively. Inspection of
the crude reaction material by NMR spectroscopy from these
reaction processes indicated that the Overman rearrangement
had not gone to completion. An increase in loading of the
palladium catalyst and the use of longer reaction times and higher
temperatures did not give any substantial improvement in the
yields of 10 and 12. The problems associated with the Overman
rearrangement of allylic trichloroacetimidates 9 and 11 may be due
to coordination of the palladium(II) catalyst with the heteroatom
and the adjacent terminal alkene preventing effective activation
and subsequent rearrangement of the allylic trichloroacetimidate
moiety.22 To overcome this problem, the rearrangement of allylic
trichloroacetimidates 9 and 11 was done under thermal conditions
resulting in a significant increase in the overall yields of the
corresponding bicyclic lactams (entries 4 and 5).
Having examined the scope of the three-step tandem sequence,
we were interested in developing an enantioselective variant. The
groups of Richards and Overman have developed a series of chiral
palladium(II) complexes such as (S)-COP–Cl 13, which catalyze
the rearrangement of allylic trichloroacetimidates in high yields
and in excellent enantioselectivity.18,23 These commercially avail-
able catalysts are finding increasingly more widespread application
for the synthesis of chiral allylic amines.24
Rearrangement of allylic trichloroacetimidate 2 using either (S)-
COP–Cl 13 or (R)-COP–Cl during the first step of the three-stage
tandem process gave bicyclic [4.3.0] lactams 14 and 15 in 70% and
53% yield, respectively and both with high enantioselectivity (89%
ee) (Table 2, entries 1 and 2).25 The use of (S)-COP–Cl 13 for
Scheme 3 Optimisation of the one-pot reaction.
Without purification, allylic trichloroacetimidate 2 was subjected
to an Overman rearrangement using bis(acetonitrile)palladium(II)
chloride (10 mol%). Grubbs first generation catalyst19 (10 mol%)
was then added and the RCM step was heated to 60 ◦C (entry 1).
The temperature was then increased to 155 ◦C to initiate the
Kharasch cyclization step which led to the isolation of bicyclic
[4.3.0] lactam 4 as a single diastereomer in 59% overall yield
from allylic alcohol 1.20 A significant amount of the cyclic
allylic trichloroacetamide (~30%), the product of the RCM step
was also isolated, suggesting that the Grubbs first generation
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Table 1 Synthesis of various bicyclic g-lactams
Table 2 Development of the asymmetric tandem process
Conclusions
In summary, a one-pot, three-step tandem process has been
developed for the direct synthesis of functionalized bicyclic [3.3.0],
[4.3.0] and [5.3.0] g-lactams from simple allylic alcohol precursors.
This process utilises a palladium catalyst to effect the Overman
rearrangement with Grubbs first generation catalyst then used for
the catalysis of both the RCM and Kharasch steps. Overall, the net
result of the tandem process is the formation of two carbon-carbon
bonds, a carbon-nitrogen bond and a carbon-chlorine bond and
using chiral palladium(II) catalysts during the first step generates
three contiguous stereogenic centres all in a single flask reaction.
Further applications of this process will be reported in due course.
Experimental
All reagents and starting materials were obtained from
commercial sources and used as received. All dry solvents were
purified using a PureSolv 500 MD solvent purification system.
All reactions were performed under an atmosphere of argon
unless otherwise mentioned. Flash column chromatography
was carried out using Fisher matrix silica 60. Macherey-Nagel
aluminium-backed plates pre-coated with silica gel 60 (UV254
)
the rearrangement of allylic trichloroacetimidate 5, gave bicyclic
[3.3.0] lactam 16 in 51% overall yield and in 94% ee (entry 3).26
were used for thin layer chromatography and were visualised by
staining with KMnO4. 1H NMR and 13C NMR spectra were
3420 | Org. Biomol. Chem., 2010, 8, 3418–3425
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©

recorded on a Bruker DPX 400 spectrometer with chemical
shift values in ppm relative to tetramethylsilane as the standard.
Assignment of 13C NMR signals is based on DEPT experiments.
Infrared spectra were recorded using Golden Gate apparatus
on a JASCO FTIR 410 spectrometer and mass spectra were
obtained using a JEOL JMS-700 spectrometer. Melting points
were determined on a Reichert platform melting point apparatus.
Optical rotations were determined as solutions irradiating
with the sodium D line (l = 589 nm) using an Autopol V
polarimeter. [a]D values are given in units 10-1 deg cm2 g-1. The
chiral HPLC methods were calibrated with their corresponding
General procedure 3: Synthesis of allylic trichloroacetimidate
followed by a one-pot Overman rearrangement/ring-closing
metathesis/Kharasch cyclization
Allylic alcohol (1 equiv.) was dissolved in dichloromethane
(20 mL) and cooled to 0 ◦C. To the solution was added 1,8-
diazabicyclo[5.4.0]undec-7-ene (0.5 equiv.) and trichloroacetoni-
trile (1.5 equiv.). The reaction mixture was allowed to warm to
room temperature before stirring for 3 h. The reaction mixture was
filtered through a short pad of silica gel and the filtrate concen-
trated in vacuo to give the allylic trichloroacetimidate, which was
used without further purification. The allylic trichloroacetimidate
was dissolved in toluene (10 mL) and transferred to a Schlenk
tube containing bis(acetonitrile)palladium(II) chloride (10 mol%).
The tube was then sealed under argon and the reaction mixture
stirred at room temperature overnight. Grubbs first-generation
catalyst (10 mol%) was added and after degassing of the solvent,
the reaction mixture was stirred at room temperature. The reaction
mixture was sealed under argon and stirred at 155 ◦C. The reaction
5
racemic mixtures. (S)-COP–Cl 13 refers to di-m-chlorobis[h -
(S)-(rR)-2-(2¢-(4¢-methylethyl)oxazolinyl)cyclopentadienyl, 1-C,
4
3¢-N)(h -tetraphenylcyclobutadiene)cobalt]dipalladium and (R)-
5
COP–Cl and refers to di-m-chlorobis[h -(R)-(rR)-2-(2¢-(4¢-methyl-
4
ethyl)oxazolinyl)cyclopentadienyl, 1-C, 3¢-N)(h -tetraphenyl-
cyclobutadiene)cobalt]dipalladium.
R
mixture was cooled, filtered through a short pad of Celiteꢀ and
General procedure 1: One Pot Swern
Oxidation/Horner–Wadsworth–Emmons reaction
washed with diethyl ether (150 mL). The solvent was removed
in vacuo to give a brown residue. Purification was carried out
by flash column chromatography using an eluent of petroleum
ether/ethyl acetate to afford the desired bicyclic lactam.
To
a stirred solution of oxalyl chloride (1.4 equiv.) in
dichloromethane (60 mL) at -78 ◦C, was added dimethyl sulfoxide
(2.5 equiv.). The reaction was stirred at -78 ◦C for 0.3 h before
slow addition of the alcohol in dichloromethane (40 mL). After a
further 0.3 h at -78 ◦C, triethylamine (5 equiv.) was added. The re-
action mixture was stirred for a further 0.5 h then allowed to warm
to room temperature and stirred for 2 h. The Horner–Wadsworth–
Emmons solution was prepared by dissolving lithium chloride
(1.8 equiv.) in acetonitrile (70 mL) followed by addition of triethyl
phosphonoacetate (1.5 equiv.) and 1,8-diazabicyclo[5.4.0]undec-7-
ene (1.5 equiv.). The mixture was stirred at room temperature for
1 h. The Swern solution was concentrated in vacuo and the Horner–
Wadsworth–Emmons solution was added to the crude residue
before stirring at room temperature overnight. The reaction was
quenched with saturated ammonium chloride solution (50 mL)
andconcentratedunder reducedpressuretogiveanorangeresidue.
The product was extracted using diethyl ether (4 ¥ 50 mL), the
organic layers combined, dried (MgSO4) and concentrated to
give a yellow oil. Purification was carried out by flash column
chromatography using an eluent of petroleum ether/diethyl ether
to afford the desired a,b-unsaturated ester.
Ethyl (2E)-2,6-heptadienoate27
Ethyl (2E)-2,6-heptadienoate was synthesised according to general
procedure 1, using 4-penten-1-ol (1.00 g, 11.6 mmol). Flash
column chromatography (petroleum ether/diethyl ether 95 : 5)
afforded the desired compound (1.17 g, 65%) as a pale yellow
oil. Spectroscopic data consistent with literature.27
n
max/cm-1
=
(neat) 2986 (CH), 1721 (CO), 1651 (C C), 1265, 1173, 1042; dH
(400 MHz, CDCl3) 1.29 (3H, t, J 7.1 Hz, OCH2CH3), 2.18–2.26
(2H, m, 5-H2), 2.27–2.35 (2H, m, 4-H2), 4.19 (2H, q, J 7.1 Hz,
OCH2CH3), 4.99–5.09 (2H, m, 7-H2), 5.75–5.86 (2H, m, 2-H
and 6-H), 6.96 (1H, dt, J 15.6, 6.7 Hz, 3-H); dC (100 MHz,
CDCl3) 14.3 (CH3), 31.5 (CH2), 32.1 (CH2), 60.3 (CH2), 115.6
(CH2), 121.8 (CH), 137.2 (CH), 148.4 (CH), 166.7 (C); m/z (CI)
155.1075 (MH+. C9H15O2 requires 155.1072), 137 (16%), 107 (17),
73 (22).
General procedure 2: Reduction of a,b-unsaturated ester using
Ethyl (2E)-2,7-octadienoate28
DIBAL-H
Ethyl (2E)-2,7-octadienoate was synthesised according to general
procedure 1, using 5-hexen-1-ol (3.00 g, 30 mmol). Flash column
chromatography (petroleum ether/diethyl ether 9 : 1) afforded the
desired compound (3.96 g, 79%) as a pale yellow oil. Spectroscopic
a,b-Unsaturated ester (1 equiv.) was dissolved in diethyl ether
(100 mL) and cooled to -78 ◦C. DIBAL-H (1 M in hexane,
2.2 equiv.) was added dropwise and the reaction mixture allowed
◦
to stir at -78 C for 3 h. The reaction mixture was then allowed
data consistent with literature.28
n
max/cm-1 (neat) 2978 (CH), 1721
=
to warm to room temperature before stirring overnight. The
reaction mixture was cooled to 0 ◦C and quenched with a saturated
ammonium chloride solution (20 mL) before stirring rapidly for 1 h
at room temperature to produce a white precipitate. The mixture
(CO), 1651 (C C), 1265, 1172, 1041; dH (400 MHz, CDCl3) 1.29
(3H, t, J 7.1 Hz, OCH2CH3), 1.56 (2H, quin., J 7.2 Hz, 5-H2), 2.05–
2.13 (2H, m, 6-H2), 2.18–2.26 (2H, m, 4-H2), 4.19 (2H, q, J 7.1 Hz,
OCH2CH3), 4.95–5.06 (2H, m, 8-H2), 5.73–5.84 (2H, m, 2-H and
7-H), 6.96 (1H, dt, J 15.7, 6.9 Hz, 3-H); dC (100 MHz, CDCl3)
14.2 (CH3), 27.1 (CH2), 31.5 (CH2), 33.0 (CH2), 60.1 (CH2), 115.1
(CH2), 121.5 (CH), 138.0 (CH), 148.8 (CH), 166.6 (C); m/z (CI)
169.1232 (MH+. C10H17O2 requires 169.1229), 141 (90%), 123 (75),
95 (100), 81 (53), 55 (32).
R
was filtered through a short plug of Celiteꢀ and washed with
diethyl ether (400 mL). The organic solvent was dried (MgSO4) and
concentrated in vacuo. Purification was carried out by flash column
chromatography using an eluent of petroleum ether/diethyl ether
to afford the desired allylic alcohol.
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Org. Biomol. Chem., 2010, 8, 3418–3425 | 3421
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Ethyl (2E)-2,8-nonadienoate29
14.4 mmol). Flash column chromatography (petroleum
ether/diethyl ether 4 : 1) afforded the desired compound (1.43 g,
89%) as a colourless oil. Spectroscopic data consistent with
Ethyl (2E)-2,8-nonadienoate was synthesised according to general
procedure 1, using 6-hepten-1-ol (1.00 g, 8.8 mmol). Flash column
chromatography (petroleum ether/diethyl ether 97 : 3) afforded
the desired compound (1.14 g, 71%) as a pale yellow oil. Spec-
literature.27
n
max/cm-1 (neat) 3325 (OH), 2924 (CH), 1643 (C C),
=
1443, 1088, 972, 910; dH (400 MHz, CDCl3) 1.35 (1H, br s, OH),
2.13–2.18 (4H, m, 4-H2 and 5-H2), 4.09 (2H, d, J 4.8 Hz, 1-H2),
4.95–5.07 (2H, m 7-H2), 5.62–5.75 (2H, m, 2-H and 3-H), 5.76–
5.88 (1H, m, 6-H); dC (100 MHz, CDCl3) 31.6 (CH2), 33.3 (CH2),
63.8 (CH2), 114.9 (CH2), 129.4 (CH), 132.4 (CH), 138.1 (CH);
m/z (CI) 113.0964 (MH+. C7H13O requires 113.0966), 95 (100%),
81 (14), 73 (13).
troscopic data consistent with literature.29
n
max/cm-1 (neat) 2932
=
(CH), 1721 (CO), 1651 (C C), 1265, 1180, 1042; dH (400 MHz,
CDCl3) 1.29 (3H, t, J 7.1 Hz, OCH2CH3), 1.37–1.53 (4H, m, 5-H2
and 6-H2), 2.06 (2H, q, J 6.9 Hz, 7-H2), 2.21 (2H, q, J 6.9 Hz, 4-
H2), 4.18 (2H, q, J 7.1 Hz, OCH2CH3), 4.92–5.04 (2H, m, 9-H2),
5.73–5.85 (2H, m, 2-H and 8-H), 6.96 (1H, dt, J 15.6, 6.9 Hz, 3-H);
dC (100 MHz, CDCl3) 14.3 (CH3), 27.5 (CH2), 28.4 (CH2), 32.0
(CH2), 33.5 (CH2), 60.2 (CH2), 114.6 (CH2), 121.4 (CH), 138.6
(CH), 149.2 (CH), 166.8 (C); m/z (CI) 183.1382 (MH+. C11H19O2
requires 183.1385), 113 (8%), 97 (7), 81 (13), 71 (15).
(2E)-Octa-2,7-dien-1-ol (1)28
(2E)-Octa-2,7-dien-1-ol (1) was synthesised according to general
procedure 2 using ethyl (2E)-2,7-octadienoate (3.88 g, 23.1 mmol).
Flash column chromatography (petroleum ether/diethyl ether
1 : 1) afforded the desired compound (2.39 g, 82%) as a colourless
Ethyl (2E)-4-allyloxybut-2-enoate
oil. Spectroscopic data consistent with literature.28
n
max/cm-1 (neat)
Ethyl (2E)-4-allyloxybut-2-enoate was synthesised according to
general procedure 1, using ethylene glycol monoallyl ether
(1.50 g, 14.7 mmol). Flash column chromatography (petroleum
ether/diethyl ether 98 : 2) afforded the desired compound (1.26 g,
50%) as a colourless oil. nmax/cm-1 (NaCl) 2982 (CH), 1720 (CO),
=
3325 (OH), 2924 (CH), 1643 (C C), 1435, 1087, 972, 910; dH
(400 MHz, CDCl3) 1.36 (1H, br s, OH), 1.49 (2H, quin, J 7.2 Hz,
5-H2), 2.03–2.11 (4H, m, 4-H2 and 6-H2), 4.10 (2H, d, J 4.6 Hz,
1-H2), 4.93–5.05 (2H, m, 8-H2), 5.60–5.74 (2H, m, 2-H and 3-H),
5.80 (1H, ddt, J 17.0, 10.2, 6.7 Hz, 7-H); dC (100 MHz, CDCl3)
28.3 (CH2), 31.6 (CH2), 33.2 (CH2), 63.6 (CH2), 114.6 (CH2), 129.2
(CH), 132.9 (CH), 138.6 (CH); m/z (CI) 109.1009 (MH+-H2O.
C8H13 requires 109.1017), 95 (16%), 81 (12), 67 (47).
=
1662 (C C), 1447, 1386, 1302, 1178, 1040, 930; dH (400 MHz,
CDCl3) 1.29 (3H, t, J 7.1 Hz, OCH2CH3), 4.03 (2H, d, J 5.5 Hz,
OCH2CHCH2), 4.15 (2H, dd, J 4.3, 1.9 Hz, 4-H2), 4.20 (2H, q, J
7.1 Hz, OCH2CH3), 5.21 (1H, d, J 10.4 Hz, OCH2CHCHH),
5.31 (1H, d, J 17.2 Hz, OCH2CHCHH), 5.85–5.97 (1H, m,
OCH2CHCH2), 6.09 (1H, dt, J 15.7, 1.9 Hz, 2-H), 6.96 (1H, dt,
J 15.7, 4.3 Hz, 3-H); dC (100 MHz, CDCl3) 14.3 (CH3), 60.4
(CH2), 68.6 (CH2), 71.7 (CH2), 117.4 (CH2), 121.3 (CH), 134.2
(CH), 144.3 (CH), 166.4 (C); m/z (CI) 171.1022 (MH+. C9H15O3
requires 171.1021), 163 (6%), 131 (10), 125 (11), 115 (31), 69 (10).
(2E)-Nona-2,8-dien-1-ol29
(2E)-Nona-2,8-dien-1-ol was synthesised according to gen-
eral procedure 2 using ethyl (2E)-2,8-nonadienoate (1.05 g,
5.77 mmol). Flash column chromatography (petroleum
ether/diethyl ether 4 : 1) afforded the desired compound (0.73 g,
90%) as a colourless oil. Spectroscopic data consistent with
literature.29
n
max/cm-1 (neat) 3341 (OH), 2924 (CH), 1643 (C C),
=
Ethyl (2E)-4-[N-allyl-N-(p-toluenesulfonyl)amino]but-2-enoate
1435, 1088, 972, 910; dH (400 MHz, CDCl3) 1.33 (1H, br s, OH),
1.36–1.44 (4H, m, 5-H2 and 6-H2), 2.01–2.10 (4H, m, 4-H2 and
7-H2), 4.09 (2H, d, J 4.9 Hz, 1-H2), 4.91–5.03 (2H, m, 9-H2),
5.59–5.74 (2H, m, 2-H and 3-H), 5.80 (1H, ddt, J 17.0, 10.2,
6.7 Hz, 8-H); dC (100 MHz, CDCl3) 28.4 (CH2), 28.6 (CH2), 32.1
(CH2), 33.6 (CH2), 68.9 (CH2), 114.4 (CH2), 129.0 (CH), 133.3
(CH), 138.9 (CH); m/z (CI) 123.1169 (MH+-H2O. C9H15 requires
123.1174), 109 (16%), 95 (12), 81 (63), 67 (17).
Ethyl (2E)-N-allyl-N-(p-toluenesulfonyl)but-2-enoate was syn-
thesised according to general procedure 1, using N-allyl-N-
(p-toluenesulfonyl)-2-aminoethanol (0.40 g, 1.56 mmol). Flash
column chromatography (petroleum ether/diethyl ether 7 : 3)
afforded the desired product (0.38 g, 75%) as a pale yellow oil.
n
max/cm-1 (NaCl) 2982 (CH), 2920 (CH), 1719 (CO), 1661 (C C),
=
1598, 1347, 1161, 1039, 762; dH (400 MHz, CDCl3) 1.28 (3H, t, J
7.1 Hz, OCH2CH3), 2.44 (3H, s, Ar-CH3), 3.80 (2H, d, J 6.4 Hz,
NCH2CHCH2), 3.92 (2H, d, J 5.6 Hz, 4-H2), 4.18 (2H, q, J 7.1 Hz,
OCH2CH3), 5.10–5.19 (2H, m, NCH2CHCH2), 5.53–5.66 (1H, m,
NCH2CHCH2), 5.90 (1H, d, J 15.6 Hz, 2-H), 6.70 (1H, dt, J 15.6,
5.6 Hz, 3-H), 7.31 (2H, d, J 8.0 Hz, 2 ¥ Ar–H), 7.71 (2H, d, J
8.0 Hz, 2 ¥ Ar–H); dC (100 MHz, CDCl3) 14.2 (CH3), 21.6 (CH3),
47.3 (CH2), 50.4 (CH2), 60.6 (CH2), 119.8 (CH2), 124.0 (CH), 127.2
(2 ¥ CH), 129.9 (2 ¥ CH), 132.2 (CH), 136.8 (C), 142.3 (CH), 143.7
(C), 166.7 (C); m/z (FAB) 324.1275 (MH+. C16H22NO4S requires
324.1270), 322 (24%), 278 (54), 224 (8), 168 (56), 155 (58), 122
(13), 91 (63), 85 (10).
(2E)-4-Allyloxybut-2-en-1-ol
(2E)-4-Allyloxybut-2-en-1-ol was synthesised according to
general procedure 2 using ethyl (2E)-4-allyloxybut-2-enoate
(0.79 g, 4.65 mmol). Flash column chromatography (petroleum
ether/diethyl ether 4 : 1) afforded the desired compound (0.49 g,
76%) as a colourless oil. nmax/cm-1 (NaCl) 3433 (OH), 2855 (CH),
=
1645 (C C), 1451, 1423, 1358, 1094, 1005; dH (400 MHz, CDCl3)
1.49 (1H, br s, OH), 3.98–4.02 (4H, m, 4-H2 and OCH2CHCH2),
4.16–4.18 (2H, m, 1-H2), 5.17–5.22 (1H, m, OCH2CHCHH), 5.26–
5.32 (1H, m, OCH2CHCHH), 5.79–5.97 (3H, m, 2-H, 3-H and
OCH2CHCH2); dC (100 MHz, CDCl3) 63.0 (CH2), 70.0 (CH2),
71.3 (CH2), 117.2 (CH2), 127.8 (CH), 132.2 (CH), 134.6 (CH);
m/z (CI) 129.0918 (MH+. C7H13O2 requires 129.0916), 111 (98%),
93 (35), 79 (100), 71 (66).
(2E)-Hepta-2,6-dien-1-ol27
(2E)-Hepta-2,6-dien-1-ol was synthesised according to gen-
eral procedure 2 using ethyl (2E)-2,6-heptadienoate (2.22 g,
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(2E)-4-[N-(allyl)-N-(p-toluenesulfonyl)amino]but-2-en-1-ol
1 h at room temperature followed by 2 h at 155 ◦C. Flash column
chromatography (petroleum ether/ethyl acetate 7 : 3) afforded the
desired compound (0.138 g, 71%) as a white solid. Spectroscopic
data as described above.
(2E)-4-[N-(Allyl)-N-(p-toluenesulfonyl)amino]but-2-en-1-ol was
synthesised according to general procedure
2 using ethyl
(2E)-4-[N-allyl-N-(p-toluenesulfonyl)amino]but-2-enoate (1.50 g,
4.64 mmol). Flash column chromatography (petroleum
ether/diethyl ether 3 : 2) afforded the desired compound (1.01 g,
78%) as viscous oil. nmax/cm-1 (NaCl) 3513 (OH), 2922 (CH), 1643
(1S*,5S*,6S*)-5,7,7-Trichloro-8-oxo-9-azabicyclo[4.3.0]nonane
(4)9b
=
(C C), 1597, 1443, 1338, 1158, 1091, 662; dH (400 MHz, CDCl3)
(1S*,5S*,6S*)-5,7,7-Trichloro-8-oxo-9-azabicyclo[4.3.0]nonane
(4) was synthesised according to general procedure 3 using (2E)-
octa-2,7-dien-1-ol (1) (0.10 g, 0.8 mmol). The reaction mixture
was stirred with Grubbs first-generation catalyst (10 mol%) and
1.79 (1H, br s, OH), 2.43 (3H, s, Ar-CH3), 3.78–3.83 (4H, m, 4-H2
and NCH2CHCH2), 4.08 (2H, d, J 4.9 Hz, 1-H2), 5.11–5.19 (2H,
m, NCH2CHCH2), 5.48–5.66 (2H, m, 3-H and NCH2CHCH2),
5.74 (1H, dt, J 15.4, 4.9 Hz, 2-H), 7.30 (2H, d, J 8.1 Hz, 2 ¥ Ar–
H), 7.70 (2H, d, J 8.1 Hz, 2 ¥ Ar–H); dC (100 MHz, CDCl3)
21.6 (CH3), 48.2 (CH2), 49.6 (CH2), 62.7 (CH2), 119.1 (CH2),
125.7 (CH), 127.2 (2 ¥ CH), 129.7 (2 ¥ CH), 132.7 (CH), 133.7
(CH), 137.2 (C), 143.4 (C); m/z (CI) 282.1169 (MH+. C14H20NO3S
requires 282.1164), 264 (100%), 212 (11), 157 (8), 128 (6).
˚
4 A molecular sieves (1.00 g) for 1 h at room temperature, before
sealing under argon and stirring for 2 h at 155 ◦C. Flash column
chromatography (petroleum ether/ethyl acetate 7 : 3) afforded the
desired compound (0.17 g, 87%) as a white solid. Spectroscopic
data as described above.
(1S*,4S*,5S*)-4,6,6-Trichloro-7-oxo-8-azabicyclo[3.3.0]octane
(6)11b
(1S*,5S*,6S*)-5,7,7-Trichloro-8-oxo-9-azabicyclo[4.3.0]nonane
(4)9b
(1S*,4S*,5S*)-4,6,6-Trichloro-7-oxo-8-azabicyclo[3.3.0]octane
(6) was synthesised according to general procedure 3 using (2E)-
hepta-2,6-dien-1-ol (0.10 g, 0.9 mmol). The reaction mixture was
(1S*,5S*,6S*)-5,7,7-Trichloro-8-oxo-9-azabicyclo[4.3.0]nonane
(4) was synthesised according to general procedure 3 using (2E)-
octa-2,7-dien-1-ol (1) (0.10 g, 0.8 mmol). The reaction mixture
was stirred with Grubbs first-generation catalyst (10 mol%) for
1 h at 60 ◦C followed by 3 h at 155 ◦C. Flash column chromatog-
raphy (petroleum ether/ethyl acetate 7 : 3) afforded the desired
compound (0.115 g, 59%) as a white so◦lid. Spectroscopic data
consistent with literature.9b mp 135–137 C, lit.9b 142–143.5 ◦C;
˚
stirred with Grubbs first-generation catalyst (10 mol%) and 4 A
molecular sieves (1.00 g) for 1 h at room temperature, before
sealing under argon and stirring for 4 h at 155 ◦C. Flash column
chromatography (petroleum ether/ethyl acetate 7 : 3) afforded the
desired compound (0.14 g, 71%) as a white solid◦. Spectroscopic
data consistent with literature.11b mp: 172–174 C, lit.11b 175–
176 ◦C; nmax/cm-1 (neat) 3264 (NH), 2932 (CH), 1690 (CO), 1427,
1273, 1049, 741; dH (400 MHz, CDCl3) 1.87–1.95 (1H, m, 2-HH),
2.00–2.09 (1H, m, 2-HH), 2.18–2.36 (2H, m, 3-H2), 3.66 (1H, dd,
J 6.4, 3.4 Hz, 5-H), 4.41–4.46 (1H, m, 1-H), 4.59–4.64 (1H, m,
4-H), 7.75 (1H, br s, NH); dC (100 MHz, CDCl3) 30.6 (CH2), 34.7
(CH2), 56.6 (CH), 61.0 (CH), 65.8 (CH), 83.1 (C), 169.0 (C); m/z
(EI) 226.9679 (M+. C7H835Cl3NO requires 226.9671), 192 (12%),
151 (96), 149 (100), 113 (71), 77 (56).
n
max/cm-1 (neat) 3256 (NH), 2924 (CH), 1690 (CO), 1427, 1273,
741; dH (400 MHz, CDCl3) 1.63–1.84 (3H, m, 3-H2 and 4-HH),
1.91–2.01 (2H, m, 2-HH and 4-HH), 2.31–2.41 (1H, m, 2-HH),
3.34 (1H, dd, J 7.0, 3.7 Hz, 6-H), 3.99 (1H, apparent q, J 7.0 Hz,
1-H), 4.62 (1H, apparent q, J 3.7 Hz, 5-H), 7.30 (1H, br s, NH);
dC (100 MHz, CDCl3) 17.5 (CH2), 28.4 (CH2), 32.2 (CH2), 50.0
(CH), 55.2 (CH), 57.1 (CH), 82.5 (C), 168.5 (C); m/z (CI) 241.9908
(MH+. C8H1135Cl3NO requires 241.9906), 208 (100), 172 (32), 157
(71), 113 (24), 81 (43).
(1S*,6S*,7S*)-6,8,8-Trichloro-9-oxo-10-azabicyclo[5.3.0]decane
(8)11b
(1S*,5S*,6S*)-5,7,7-Trichloro-8-oxo-9-azabicyclo[4.3.0]nonane
(4)9b
(1S*,6S*,7S*)-6,8,8-Trichloro-9-oxo-10-azabicyclo[5.3.0]decane
(8) was synthesised according to general procedure 3 (at a
concentration of 0.009 M) using (2E)-octa-2,7-dien-1-ol (0.05 g,
0.36 mmol). The reaction was stirred with Grubbs first-generation
catalyst (10 mol%) for 48 h at 50 ◦C. A second quantity of Grubbs
first-generation catalyst (5 mol%) was then added and the reaction
stirred for a further 24 h at 50 ◦C. A third quantity of Grubbs first-
generation catalyst (5 mol%) was added and the reaction stirred for
a further 24 h at 50 ◦C. A final quantity of Grubbs first-generation
catalyst (5 mol%) was added and the reaction stirred for a final
(1S*,5S*,6S*)-5,7,7-Trichloro-8-oxo-9-azabicyclo[4.3.0]nonane
(4) was synthesised according to general procedure 3 using (2E)-
octa-2,7-dien-1-ol (1) (0.10 g, 0.8 mmol). The reaction mixture was
stirred with Grubbs first-generation catalyst (10 mol%) for 1 h
at 60 ◦C. A further quantity of Grubbs first-generation catalyst
(5 mol%) was added to the reaction before stirring for 2 h at
155 ◦C. Flash column chromatography (petroleum ether/ethyl
acetate 7 : 3) afforded the desired compound (0.141 g, 73%) as
a white solid. Spectroscopic data as described above.
◦
˚
24 h at 50 C. To the cooled reaction, 4 A molecular sieves (1.00 g)
were added before sealing under argon and stirring at 155 ◦C for
2 h. Flash column chromatography (petroleum ether/ethyl acetate
7 : 3) afforded the desired compound (0.06 g, 60%) as a white so◦lid.
Spectroscopic data consistent with literature.11b mp 208–210 C,
(1S*,5S*,6S*)-5,7,7-Trichloro-8-oxo-9-azabicyclo[4.3.0]nonane
(4)9b
(1S*,5S*,6S*)-5,7,7-Trichloro-8-oxo-9-azabicyclo[4.3.0]nonane
(4) was synthesised according to general procedure 3 using (2E)-
octa-2,7-dien-1-ol (1) (0.10 g, 0.8 mmol). The reaction mixture
was stirred with Grubbs first-generation catalyst (10 mol%) for
◦
lit.11b 206–208 C; nmax/cm-1 (neat) 3194 (NH), 2932 (CH), 1705
(CO), 1443, 1281, 1026, 849, 772; dH (400 MHz, CDCl3) 1.22–
1.35 (1H, m, 3-HH), 1.45–1.59 (1H, m, 4-HH), 1.73–1.84 (2H, m,
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2-H2), 1.85–1.97 (2H, m, 3-HH and 4-HH), 1.98–2.09 (1H, m, 5-
HH), 2.32–2.40 (1H, m, 5-HH), 3.41 (1H, dd, J 10.1, 8.3 Hz, 7-H),
3.75–3.82 (1H, m, 1-H), 4.47–4.53 (1H, m, 6-H), 7.69 (1H, br s,
NH); dC (100 MHz, CDCl3) 27.4 (CH2), 29.0 (CH2), 31.7 (CH2),
38.7 (CH2). 57.1 (CH), 59.0 (CH), 60.2 (CH), 83.9 (C), 168.8 (C);
m/z (CI) 256.0063 (MH+. C9H1335Cl3NO requires 256.0063), 222
(49), 186 (12), 152 (26), 107 (41), 91 (6).
(CH), 82.6 (C), 127.5 (2 ¥ CH), 130.2 (2 ¥ CH), 133.4 (C), 144.6
(C), 167.5 (C); m/z (FAB) 398.9912 (MH+. C14H1635Cl237ClN2O3S
requires 398.9919), 363 (6%), 307 (7), 243 (5), 155 (89), 137 (100),
121 (14), 109 (11).
(1S,5S,6S)-5,7,7-Trichloro-8-oxo-9-azabicyclo[4.3.0]nonane (14)
(1S,5S,6S)-5,7,7-Trichloro-8-oxo-9-azabicyclo[4.3.0]nonane (14)
was synthesised according to general procedure 3 using (2E)-
octa-2,7-dien-1-ol (1) (0.10 g, 0.8 mmol). The reaction was stirred
with (S)-COP–Cl (3 mol%) for 36 h at 38 ◦C. A second quantity
of (S)-COP–Cl (3 mol%) was added and the solution stirred
at 38 ◦C for 72 h. A final quantity of (S)-COP–Cl (3 mol%)
was added and the solution stirred at 38 ◦C for a further 24 h.
Grubbs first-generation catalyst (10 mol%) was added and after
degassing of the solvent, the reaction mixture was stirred for 1 h
(1R*,5R*,6S*)-3-Oxa-5,7,7-trichloro-8-oxo-9-
azabicyclo[4.3.0]nonane (10)
(1R*,5R*,6S*)-3-Oxa-5,7,7-trichloro-8-oxo-9-azabicyclo[4.3.0]-
nonane (10) was synthesised according to general procedure 3
using (2E)-4-allyloxybut-2-en-1-ol (0.10 g, 0.78 mmol). The allylic
trichloroacetimidate was dissolved in toluene and stirred with
potassium carbonate (0.03 g, 0.22 mmol) in a sealed tube at
˚
◦
at room temperature. 4 A Molecular sieves (1.00 g) were then
140 C for 72 h. Grubbs first-generation catalyst (10 mol%) was
added, the reaction sealed under argon and stirred at 155 ◦C
for 3 h. Flash column chromatography (petroleum ether/ethyl
acetate 7 : 3) afforded the desired compound (0.20 g, 70%) as a
white solid. Chiral HPLC (Chiralcel IB column) analysis using
4% isopropanol in hexane as the elution solvent indicated 89% ee.
[a]2D4 +59.2 (c 1.2, CHCl3). All other spectroscopic data matched
that previously reported for (1S*,5S*,6S*)-5,7,7-trichloro-8-oxo-
9-azabicyclo[4.3.0]nonane (4).
added and after degassing of the solvent, the reaction mixture was
stirred at room temperature for 3 h. A second quantity of Grubbs
first-generation catalyst (5 mol%) was added and the reaction
˚
stirred for a further 1 h at room temperature. 4 A Molecular
sieves (1.00 g) were then added, the reaction sealed under argon
and heated at 155 ◦C for 3 h. Flash column chromatography
(petroleum ether/ethyl acetate 7 : 3) afforded the desired bicyclic
lactam (0.10 g, 52%) as a white solid. mp 188–190 ◦C; nmax/cm-1
(neat) 3139 (NH), 2864 (CH), 1752 (CO), 1711, 1367, 1096, 1033,
909, 834, 763; dH (400 MHz, CDCl3) 3.21 (1H, dd, J 8.0, 5.3 Hz,
6-H), 3.42 (1H, dd, J 12.0, 9.3 Hz, 4-HH), 3.77 (1H, dd, J 12.9,
2.8 Hz, 2-HH), 3.98–4.05 (1H, m, 5-H), 4.05–4.11 (2H, m, 1-H
and 2-HH), 4.16 (1H, dd, J 12.0, 5.3 Hz, 4-HH), 7.59 (1H, br s,
NH); dC (100 MHz, CDCl3) 50.1 (CH), 51.1 (CH), 56.7 (CH), 67.3
(CH2), 70.7 (CH2), 84.0 (C), 168.7 (C); m/z (CI) 243.9695 (MH+.
C7H935Cl3NO2 requires 243.9699), 210 (68%), 174 (38), 140 (18),
107 (42).
(1R,5R,6R)-5,7,7-Trichloro-8-oxo-9-azabicyclo[4.3.0]nonane (15)
(1R,5R,6R)-5,7,7-Trichloro-8-oxo-9-azabicyclo[4.3.0]nonane (15)
was synthesised according to general procedure 3 using (2E)-octa-
2,7-dien-1-ol (1) (0.1 g, 0.8 mmol). The reaction was stirred with
(R)-COP–Cl (3 mol%) for 36 h at 38 ◦C. A second quantity of
(R)-COP–Cl (3 mol%) was added and the solution stirred at 38 ◦C
for 72 h. A final quantity of (R)-COP–Cl (3 mol%) was added and
the solution stirred at 38 ◦C for a further 24 h. Grubbs first-
˚
generation catalyst (10 mol%) and 4 A molecular sieves (1.00
g) were added and after degassing of the solvent, the reaction
mixture was stirred at room temperature for 1 h followed by 3 h
at 155 ◦C. Flash column chromatography (petroleum ether/ethyl
acetate 7 : 3) afforded the desired compound (0.10 g, 53%) as a
white solid. Chiral HPLC (Chiralcel IB column) analysis using
4% isopropanol in hexane as the elution solvent indicated 89% ee.
[a]2D4 -63.5 (c 1.3, CHCl3). All other spectroscopic data matched
that previously reported for (1S*,5S*,6S*)-5,7,7-trichloro-8-oxo-
9-azabicyclo[4.3.0]nonane (4).
(1R*,5R*,6S*)-3-(p-Toluenesulfonyl)-5,7,7-trichloro-8-oxo-3,9-
diazabicyclo[4.3.0]nonane (12)
(1R*,5R*,6S*)-3-(p-Toluenesulfonyl)-5,7,7-trichloro-8-oxo-3,9-
diazabicyclo[4.3.0]nonane (12) was synthesised according to gen-
eral procedure 3 using (2E)-4-[N-(allyl)-N-(p-toluenesulfonyl)-
amino]but-2-en-1-ol (0.10 g, 0.36 mmol). The allylic trichloroace-
timidate was dissolved in toluene and stirred with potassium
carbonate (0.03 g, 0.22 mmol) in a sealed tube at 140 ◦C for
136 h. Grubbs first-generation catalyst (15 mol%) was added and
after degassing the solvent, the reaction mixture was stirred at
(1S,4S,5S)-4,6,6-Trichloro-7-oxo-8-azabicyclo[3.3.0]octane (16)
˚
room temperature for 1 h. 4 A Molecular sieves (1.00 g) were then
added, the reaction sealed under argon and stirred at 155 ◦C for
3 h. Flash column chromatography (petroleum ether/ethyl acetate
7 : 3) afforded the desired bicyclic lactam (0.06 g, 39%) as a white
solid. mp 184–186 ◦C; nmax/cm-1 (neat) 3193 (NH), 2915 (CH),
2898 (CH), 1740 (CO), 1712, 1343, 1237, 1171, 1090, 869, 744; dH
(400 MHz, CDCl3) 2.45 (3H, s, Ar-CH3), 3.11 (1H, dd, J 13.0,
7.4 Hz, 4-HH), 3.18 (1H, apparent t, J 5.8 Hz, 6-H), 3.28 (1H, dd,
J 13.0, 4.2 Hz, 2-HH), 3.48 (1H, dd, J 13.0, 5.8 Hz, 2-HH), 3.81
(1H, dd, J 13.0, 4.3 Hz, 4-HH), 4.16–4.21 (1H, m, 1-H), 4.27–4.33
(1H, m, 5-H), 7.06 (1H, br s, NH), 7.36 (2H, d, J 8.2 Hz, 2 ¥
Ar–H), 7.67 (2H, d, J 8.2 Hz, 2 ¥ Ar–H); dC (100 MHz, CDCl3)
21.6 (CH3), 46.5 (CH2), 49.3 (CH), 50.8 (CH2), 51.4 (CH), 56.4
(1S,4S,5S)-4,6,6-Trichloro-7-oxo-8-azabicyclo[3.3.0]octane (16)
was synthesised according to general procedure 3 using (2E)-
hepta-2,6-dien-1-ol (0.10 g, 0.9 mmol). The reaction was stirred
with (S)-COP–Cl (3 mol%) for 36 h at 38 ◦C. A second quantity
of (S)-COP–Cl (3 mol%) was added and the solution stirred
at 38 ◦C for 72 h. A final quantity of (S)-COP–Cl (3 mol%)
was added and the solution stirred at 38 ◦C for a further 24 h.
Grubbs first-generation catalyst (10 mol%) was added and after
degassing of the solvent, the reaction mixture was stirred at room
˚
temperature for 1 h. 4 A Molecular sieves (1.00 g) were then
added, the reaction sealed under argon and stirred at 155 ◦C
for 4 h. Flash column chromatography (petroleum ether/ethyl
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©

acetate 7 : 3) afforded the desired compound (0.10 g, 51%) as a
white solid. Chiral HPLC (Chiralcel IB column) analysis using
4% isopropanol in hexane as the elution solvent indicated 94% ee.
[a]2D4 +45.5 (c 0.5, CHCl3). All other spectroscopic data matched
that previously reported for (1S*,4S*,5S*)-4,6,6-trichloro-7-oxo-
8-azabicyclo[3.3.0]octane (6).
10 B. Schmidt and M. Pohler, J. Organomet. Chem., 2005, 690,
5552.
11 (a) J. A. Tallarico, L. M. Malnick and M. L. Snapper, J. Org. Chem.,
1999, 64, 344; (b) B. A. Seigal, C. Fajardo and M. L. Snapper, J. Am.
Chem. Soc., 2005, 127, 16329.
12 (a) C. D. Edlin, J. Faulkner and P. Quayle, Tetrahedron Lett., 2006,
47, 1145; (b) C. D. Edlin, J. Faulkner, D. Fengas, M. Helliwell, C. K.
Knight, D. House, J. Parker, I. Preece, P. Quayle, J. Raftery and S. N.
Richards, J. Organomet. Chem., 2006, 691, 5375.
13 D. E. Fogg and E. N. dos Santos, Coord. Chem. Rev., 2004, 248,
2365.
Acknowledgements
14 R. E. Ireland and D. W. Norbeck, J. Org. Chem., 1985, 50, 2198.
15 The Masamune-Roush conditions for the HWE step were used. For
reference see: M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld,
S. Masumune, W. R. Roush and T. Sakai, Tetrahedron Lett., 1984, 25,
2183.
Financial support from the Scottish Funding Council, the Univer-
sity of Glasgow and the Schering Plough Corporation is gratefully
acknowledged.
16 For synthesis of ethylene glycol monoallyl ether, see: G. H. Lee, E. B.
Choi, E. Lee and C. S. Pak, J. Org. Chem., 1994, 59, 1428.
17 For synthesis of N-allyl-N-(p-toluenesulfonyl)-2-aminoethanol, see:
M. Poornachandran and R. Raghunathan, Tetrahedron, 2008, 64,
6461.
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20 The relative stereochemistry of bicyclic lactam 4 was determined using
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21 L. A. Paquette, Ed. Encyclopaedia of Reagents for Organic Synthesis,
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3 (a) B. M. Trost, Science, 1991, 254, 1471; (b) P. A. Wender, S. T. Handy
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